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(Journal of Leukocyte Biology. 2007;82:265-271.)
© 2007 by Society for Leukocyte Biology

Regulation of TLR4 signaling and the host interface with pathogens and danger: the role of RP105

Senad Divanovic*, Aurelien Trompette*, Lisa K. Petiniot*, Jessica L. Allen*, Leah M. Flick*, Yasmine Belkaid{dagger}, Rajat Madan*, Jennifer J. Haky* and Christopher L. Karp*,1

* Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; and
{dagger} Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA

1 Correspondence: Division of Molecular Immunology, Cincinnati Children’s Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. E-mail: chris.karp{at}chmcc.org

ABSTRACT

As all immune responses have potential for damaging the host, tight regulation of such responses—in amplitude, space, time and character—is essential for maintaining health and homeostasis. It was thus inevitable that the initial wave of papers on the role of Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) in activating innate and adaptive immune responses would be followed by a second wave of reports focusing on the mechanisms responsible for restraining and modulating signaling by these receptors. This overview outlines current knowledge and controversies about the immunobiology of the RP105/MD-1 complex, a modulator of the most robustly signaling TLR, TLR4.

Key Words: MD-1 • endogenous ligand • counter-regulation

INTRODUCTION

Immunologists have traditionally focused on the molecular mechanisms responsible for the activation of immune responses. Immune responses are energy-intensive, however, and all immune responses have the potential for damaging the host. Such responses are thus tightly controlled in amplitude, space, time, and character. Theoretical and experimental recognition of this has led to growing literature about the molecular mechanisms underlying the active process of immune counter-regulation. A series of overlapping mechanisms has been defined, including specialized cell types (e.g., regulatory T cells, Tr1 cells, and Th3 cells), inhibitory cytokines (e.g., IL-10 and TGF-β), lipid mediators (e.g., resolvins and lipoxins), ligands (e.g., CTLA-4, PD-1, and TIM-3), enzymes (e.g., inducible NO synthase and indolamine 2,3-dioxygenase), and signaling inhibitors (e.g., SOCS proteins, and PIAS proteins).

The clinical importance of counter-regulation in the innate immune system is easily appreciated. Although innate immune responses that are disrupted, delayed or of insufficient vigor can lead to a failure to control infection, excessive or inappropriate inflammation can be harmful or even fatal. The hyperinflammatory responses that characterize sepsis and the systemic inflammatory response syndrome provide paradigmatic examples. There has thus been considerable, recent interest in understanding how signaling by TLRs, NLRs, and RLRs—critical innate immune receptors that signal the presence of conserved microbial molecular structures—is regulated. The bulk of the data published to date focuses on regulation of TLR signaling.

TLR signaling is controlled at a variety of levels. Compartmentalization of TLR expression by cell type and location provides one clear mechanism of regulation [1 ]. Another mode of control is the phenomenon of endotoxin tolerance, the secondary blunting of a subset of microbial, product-driven responses. A particular instance of a more general phenomenon of activation-induced macrophage reprogramming, the molecular mechanisms underlying endotoxin tolerance remain controversial [2 , 3 ]. Other mechanisms for modulating TLR signaling include: the regulated degradation of TLR ligands [4 ]; inhibitory interactions with extracellular matrix components [5 ]; TLR-driven up-regulation of counter-regulatory cells and inhibitory cytokines and lipid mediators [6 7 8 ]; signaling cross-talk between TLRs and other immune receptors activated during inflammatory responses (e.g., complement receptors and FcRs) [9 , 10 ]; and TLR-driven apoptosis [11 ]. As outlined in Table 1 , several direct, negative regulators of TLR signaling have also been identified (reviewed in ref. [12 ]).


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  		Table 1. Endogenous Negative Regulators of TLR Signaling

It will be noted that there appears to be an over-representation of inhibitors that act on TLR4. This is not biologically implausible. In addition to being the most heavily studied TLR, TLR4 is the most robustly signaling TLR—something attributable to its ability to recruit all four known TIR-containing signaling adaptor molecules [34 ]. TLR4 also stands out for another reason. TLRs signal the presence, not only of microbe-associated molecular patterns but also of a variety of structures generated or unmasked during tissue injury and inflammation—damage-associated molecular patterns [35 ]. These include degradation products of endogenous tissue matrix macromolecules (e.g., hyaluronan fragments and heparan sulfate), endogenous molecules whose expression is up-regulated during injury or inflammation (e.g., fibronectin extra domain A, and β-defensin 2), molecules released by necrotic cells [e.g., high mobility group box 1 (HMGB1), heat shock proteins (HSPs), and chromatin/Ig complexes], and molecules altered by oxidation (e.g., minimally oxidized LDL) [36 37 38 39 40 41 42 ]. It is notable that most of these putative endogenous ligands have been shown to signal through TLR4. Given the role of TLR4 in LPS signaling, the possibility of reagent contamination has led to close scrutiny of this literature [43 ]. Some endogenous ligands, such as HMGB1 and HSPs, may well not engage TLRs directly but act as chaperones to bring endogenous and exogenous ligands to TLR4 and other TLRs. Overall, however, the findings have largely held up, despite controversy over particular ligands. This might well be expected, given the close resemblance of sterile and infectious inflammation [44 ]. Indeed, the likely physiological (and pathophysiological) role of endogenous TLR4 ligands in tissue injury and inflammation has been underscored by TLR4 dependence of the degree of inflammation, pathology, and functional damage in several in vivo models of nonmicrobial tissue damage, including ischemia-reperfusion injury, neuropathy after nerve transection, and bleomycin- and ozone-induced lung damage [45 46 47 48 ].

The TLR4 homologue, RP105, appears to be a biologically important modulator of TLR4 signaling. This overview outlines the current state of knowledge about RP105 as a regulator of TLR4 signaling and TLR4-driven immune responses.

RP105/MD-1: DISCOVERY AND FUNCTIONAL ANALYSIS IN B CELLS

RP105 was discovered originally in mouse B cells. An antibody raised against the surface of mature B cells was found to drive B cell proliferation and protection from subsequent radiation- or dexamethasone-induced apoptosis [49 ]. Cloning of human and mouse RP105 revealed a type I transmembrane protein structurally similar to TLRs, with an extracellular leucine-rich repeat domain and the pattern of juxtamembrane cysteine residues conserved among the TLRs. In contrast to TLRs, however, RP105 lacks a TIR domain, containing only six to 11 intracytoplasmic amino acids [50 51 52 53 ]. RP105 shares another striking similarity to TLR4: TLR4 signaling (of LPS, at least) is dependent on a secreted, extracellularly associated accessory protein, MD-2 [54 55 56 57 ]. Surface expression and activity of RP105 are similarly dependent on the MD-2 homologue, MD-1 [58 59 60 ].

Functional analysis of RP105 was first pursued in B cells and in B cell lines. Anti-RP105-driven B cell proliferation has been examined extensively [49 , 59 , 61 62 63 64 ]. Such B cell proliferation is associated with increased expression of MHC Class II, CD80, and CD86. The proliferative response is inhibited by subsequent cross-linking of sIgM, which induces B cell growth arrest and apoptosis [61 , 64 ]. Anti-RP105-mediated B cell proliferation appears to involve signaling through the Lyn/CD19/Vav complex, along with protein kinase CβI/II and the Erk2-specific MAPK kinase, MEK [62 , 64 ]. Given the short, intracytoplasmic tail of RP105, such signaling may well be a result of a (yet-unidentified) B cell-specific, RP105-associated protein. Alternatively, it is possible that anti-RP105-mediated proliferation is of little biological relevance: No endogenous or exogenous ligand for RP105 has been found, and antibody-driven cross-linking of RP105 may drive nonphysiological aggregation of signaling molecules, which are associated with RP105, directly or indirectly, in membrane microdomains.

LPS-induced B cell proliferation is dependent on TLR4. However, the analysis of RP105-deficient mice demonstrated a role for RP105 in LPS-driven responses by B cells as well. B cells from RP105-deficient mice exhibit reduced LPS-driven proliferative responses, despite normal, proliferative responses to anti-IgM and anti-CD40 [63 ]. Such mice have also been reported to have variable (and variably isotype-specific), diminished humoral immune responses when LPS is given as an adjuvant for T cell-independent antigens [63 , 65 ].

Functional analysis of RP105 has also been pursued in the B cell line Ba/F3. Of note, cross-linking of RP105 on transfected Ba/F3 cells does not up-regulate proliferation [50 , 63 ]. Similarly, transfection with RP105 plus MD-1 does not confer LPS sensitivity on such cells, as measured by NF-{kappa}B-driven luciferase activity [63 ].

RP105/MD-1: NEGATIVE REGULATOR OF TLR4/MD-2 SIGNALING

RP105 turned out not to be B cell-specific (following the path of a long series of "B cell-specific" molecules, including NF-{kappa}B). In fact, RP105 expression mirrors that of TLR4 on myeloid cells, including monocytes, macrophages, and dendritic cells (DC) [13 ]. Further, formal phylogenetic analysis demonstrated that RP105 belongs specifically to the TLR4 subfamily of TLRs [13 ]. Together with the structure of RP105, these findings led us to the hypothesis that RP105 is actually an inhibitor of TLR4 signaling. Indeed, we have demonstrated that RP105/MD-1 is a specific inhibitor of TLR4 signaling in human embryonic kidney (HEK)293 cells. Such inhibition is independent of the intracellular domain of RP105 [13 ]. Coimmunoprecipitation (co-IP) techniques were used to probe the association of RP105–MD-1 with TLR4–MD-2. These complexes co-IP bidirectionally, demonstrating physical association between TLR4–MD-2 and RP105–MD-1 [13 ]. Of note, MD-1 and MD-2 also co-IP bidirectionally when expressed alone, suggesting that MD-1–MD-2 heterodimerization provides the point of contact between TLR4–MD-2 and RP105–MD-1 [13 ]. LPS has been shown to bind directly to MD-2, leading to the association of LPS/MD-2 complexes with TLR4, and to TLR4 signaling [66 ]. Incubation of biotinylated LPS with TLR4-expressing HEK293 cells allows for precipitation of TLR4 (and MD-2) only in the presence of MD-2 expression. Notably, coexpression of RP105–MD-1 in this system inhibits LPS–TLR4–MD-2 complex formation, providing direct evidence that RP105–MD-1 inhibits LPS signaling complex formation [13 ]. The fact that, consistent with previously reported data [67 ], no direct interactions between LPS and RP105–MD-1 are demonstrable indicates that RP105–MD-1-mediated interference with LPS signaling complex formation is not a result of RP105–MD-1 acting as a molecular sink for LPS [13 ]. Our current model is thus one in which RP105–MD-1 interacts directly with the TLR4 signaling complex, inhibiting its ability to interact with a microbial ligand.

Of note, in addition to being implicated directly in the mechanism of modulation of TLR4 complex signaling, MD-1 is essential for surface expression of RP105 [13 , 59 ]. This contrasts somewhat with the situation with MD-2. It was reported initially that MD-2 was necessary for surface expression and signaling by TLR4 [68 ]. In fact, although MD-2 is necessary for LPS signaling (and is the LPS-binding part of the TLR4 signaling complex), surface expression of TLR4 is not dependent on MD-2 [69 ]. Whether MD-2 is necessary for TLR4 signaling in response to endogenous ligands remains to be examined.

Using genetic models, we have also shown that RP105 regulates LPS-driven TLR4 signaling in primary mouse DC and macrophages, inhibiting the production of cytokines dependent on both MAL/MyD88 and TRIF/TRIF pathways. Further, we have demonstrated that RP105 is a physiological regulator of in vivo responses to LPS: RP105-deficient mice produce significantly more systemic TNF and exhibit significant acceleration and amplification of endotoxicity in response to LPS challenge [13 ].

The in vivo administration of a purified TLR ligand, although of obvious use in mechanistic studies, has its artificial side. We thus examined the function and biological relevance of RP105 during the complexities of microbial infection. TLR4 has been reported to be essential for efficient control of Leishmania major infection [70 , 71 ], although to date, no TLR4 ligand has been identified in this protozoan. The onset of the adaptive immune response to L. major is heralded by the development of a lesion at the site of infection, which marks the end of the incubation period. Given the published data about TLR4 and L. major, we hypothesized that the absence of RP105 would lead to an acceleration of immune responses to this protozoan. This was indeed the case. After low-dose infection (3x103 metacyclic L. major promastigotes), RP105-deficient mice exhibited an abbreviation of the incubation period, with significantly increased lesion size early in infection (Fig. 1 )—albeit with similar overall control of parasite burden (data not shown). With slightly higher infective doses, no such change in very early events was seen; however, RP105-deficient mice exhibited attenuated disease, with smaller lesions and more rapid clearance of parasites (data not shown). Of note, given the reported effects of RP105 on B cell function, quantification of Leishmania-specific Ig levels in serum from wild-type and RP105-deficient mice has revealed that the absence of RP105 is associated with increased levels of L. major-specific IgG. Whether these increases are B cell-autonomous remains to be defined, although it is worth pointing out in this context that the RP105-negative subset of peripheral blood B cells in patients with systemic lupus erythematosis is highly activated and responsible for autoantibody production [72 ].


Figure 1
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  		Figure 1. Accelerated lesion development and heightened immune response in RP105-deficient mice after L. major infection. Wild-type (WT) mice (open bars) and RP105–/– mice (solid bars) were challenged intradermally with 3 x 103 metacyclic L. major promastigotes. (a) Lesion size; (b) lesional leukocyte number (4 weeks); (c) draining lymph node leukocyte number (4 weeks); (d) soluble Leishmania antigen-driven IFN-{gamma} production by draining lymph node cells (4 weeks). Data represent mean ± SEM of eight animals/group. *, P < 0.04 (Student’s t-test).

We have further examined the function and biological relevance of RP105 in a pathogen-independent, TLR-dependent model of injury. Activation of TLR signaling by commensal bacteria in the gut, as well as by endogenous TLR ligands in the lung, has been shown to be critical for mucosal epithelial homeostasis and protection from injury. In the colon, genetic ablation of TLR4 signaling leads to exacerbated disease in response to dextran sodium. sulfate-induced colitis, a mouse model of inflammatory bowel disease [73 , 74 ]. In the lung, TLR4–/–/TLR2–/– and MyD88–/– mice exhibit decreased survival and enhanced epithelial cell apoptosis after bleomycin-induced airway epithelial injury [75 ]. In the bleomycin model, this has been tied, mechanistically, to ablation of signaling by an endogenous TLR ligand: degradation products derived from hyaluronan. Noble and co-workers [75 ] have proposed that hyaluronan fragment/TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury. TLR use by hyaluronic acid fragments remains somewhat controversial: Exclusive use of TLR4 and/or TLR2 has been reported [42 , 75 , 76 ]. Given the role of RP105 in inhibiting TLR4 signaling, we hypothesized that RP105-deficient mice would be protected in the bleomycin model of acute lung injury. Indeed, genetic deletion of RP105 is associated with significant protection from mortality induced by high-dose bleomycin challenge (data not shown).

Thus, RP105 appears to act as a biologically important inhibitor of TLR4 signaling in microbial and nonmicrobial models. Others have also reported congruent data in in vivo models of alloimmunity [77 ].

RE-EXAMINING THE ROLE OF RP105 IN B CELLS

The above data, indicating that RP105/MD-1 acts as an inhibitor of TLR4 signaling in cell lines and primary myeloid cells, and in vivo, stand in apparent opposition to data published about the role of RP105 in B cells. Splenic B cells from RP105-deficient mice are reported to have blunted proliferative responses to LPS, an observation that we have replicated and that has been interpreted to mean that RP105 facilitates TLR4 signaling in B cells. It should be noted that among splenic B cells, early proliferation in response to LPS is limited to marginal zone B cells (MZB) and transitional type II B cells; splenic follicular B (FOB) cells do not exhibit early, LPS-driven proliferation [78 79 80 ]. Similarly, MZB cells are "primed" to secrete IgM rapidly in response to LPS stimulation; FOB cells take several days for this secretory response to become evident [80 ]. After a delay, FOB cells do exhibit proliferative and IgM secretory responses to LPS, but these responses are small, relative to those of MZB cells [78 79 80 ]. Of interest, whereas TLR4 expression is similar in MZB and FOB cells, the former actually has higher levels of RP105 expression [80 ]. Given this compartmentalization of LPS responsiveness, it is possible that the blunted LPS-driven proliferative response in the absence of RP105 is artifactual, resulting from the presence of fewer such cells in RP105-deficient mice. This is not the case, however. We and others [63 ] have found no differences in the percentages of such cells in RP105-deficient mice compared with wild-type littermate controls (data not shown). How might RP105 regulate LPS responses differently in myeloid cells and B cells? It is reasonable to suspect that dichotomous effects of RP105 on TLR4 signaling in B cells and myeloid cells might be a result of differential interactions with cell surface molecular partners in these different cell types. We previously proposed a model [13 ] that focuses on the widely differing expression of TLR4 on these different cell types: greater on myeloid cells; barely detectable on B cells [63 , 81 ]. TLR4 multimerization appears to be necessary for signaling [66 ]. Although TLR4–MD-2 would be expected to have a higher affinity for homodimerization than for heterodimerization with RP105–MD-1, our data suggest the likelihood that homo- and heterodimers can multimerize with further TLR4–MD-2 complexes [13 ]. This suggests the possibility that when TLR4–MD-2 is highly expressed (e.g., on myeloid cells), lower affinity, heterodimeric interactions inhibit TLR4 multimerization and signaling. In contrast, when TLR4 is limiting (e.g., on B cells), such heterodimeric interactions might serve to facilitate further TLR4 recruitment and signaling. However, the situation may be less complex. RP105 may simply be an inhibitor of TLR4 signaling in B cells as well as myeloid cells, something that may have been obscured by focusing on proliferation as a read-out of signaling. The question remains open.

CONCLUDING REMARKS

In addition to the above perplexities over the biological role of RP105/TLR4 interactions in modulating B cell function, numerous questions about the immunobiology of RP105/MD-1 remain. Is RP105 coexpressed with TLR4 on nonimmune cells? What role does subcellular localization play in regulating interactions between RP105/MD-1 and TLR4/MD-2? What is the biological role of RP105-mediated modulation of TLR signaling to endogenous ligands? How specific is RP105 for modulating TLR4 signaling? (Notably, Miyake and colleagues [65 ] have reported recently that RP105-deficient B cells have suppressed, proliferative responses, not only to lipid A (a TLR4 ligand) but also to Pam3CysK4 (a TLR2/TLR1 ligand) and macrophage-activating lipopeptide-2 (a TLR2/TLR6 ligand). The fact that, like CD14, MD-2 has been reported to facilitate some TLR2-mediated responses [82 ] provides a potential mechanism for such observations, but the latter report remains to be validated).

More generally, our understanding of the biology of negative regulators of TLR signaling is partial at best. To date, they have been studied in isolation in reductive systems. They appear to have nonredundant functions, but there is an inherent bias toward publishing positive results and hence, toward devising experimental conditions to bring out nonredundant functions. It will be important to try to understand how the plethora of described negative regulators act in concert, especially in the context of complex inflammatory processes involving signaling by multiple pattern recognition (and other) receptors. A broader and deeper understanding of these issues may well lead to novel therapeutic approaches to the rapidly expanding number of diseases shown to be marked by dysregulated or maladaptive, inflammatory responses.

ACKNOWLEDGEMENTS

This work was supported in part by grants from the National Institutes of Health (AI063183, AI057992, and T32 AI055406). We thank F. Finkelman, D. Rawlings, and A. Tarakhovsky for helpful discussions.

Received April 7, 2007; accepted April 9, 2007.

REFERENCES

    1
  1. Backhed, F., Hornef, M. (2003) Toll-like receptor 4-mediated signaling by epithelial surfaces: necessity or threat? Microbes Infect. 5,951-959[CrossRef][Medline]
    2. 2
  2. Wysocka, M., Robertson, S., Riemann, H., Caamano, J., Hunter, C., Mackiewicz, A., Montaner, L. J., Trinchieri, G., Karp, C. L. (2001) Il-12 suppression during experimental endotoxin tolerance: dendritic cell loss and macrophage hyporesponsiveness J. Immunol. 166,7504-7513[Abstract/Free Full Text]
    3. 3
  3. Cross, A. S. (2002) Endotoxin tolerance-current concepts in historical perspective J. Endotoxin Res. 8,83-98[CrossRef][Medline]
    4. 4
  4. Lu, M., Zhang, M., Takashima, A., Weiss, J., Apicella, M. A., Li, X. H., Yuan, D., Munford, R. S. (2005) Lipopolysaccharide deacylation by an endogenous lipase controls innate antibody responses to Gram-negative bacteria Nat. Immunol. 6,989-994[CrossRef][Medline]
    5. 5
  5. Brunn, G. J., Bungum, M. K., Johnson, G. B., Platt, J. L. (2005) Conditional signaling by Toll-like receptor 4 FASEB J. 19,872-874[Abstract/Free Full Text]
    6. 6
  6. Samarasinghe, R., Tailor, P., Tamura, T., Kaisho, T., Akira, S., Ozato, K. (2006) Induction of an anti-inflammatory cytokine, IL-10, in dendritic cells after Toll-like receptor signaling J. Interferon Cytokine Res. 26,893-900[CrossRef][Medline]
    7. 7
  7. Aliberti, J., Hieny, S., Reis e Sousa, C., Serhan, C. N., Sher, A. (2002) Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity Nat. Immunol. 3,76-82[CrossRef][Medline]
    8. 8
  8. Sutmuller, R. P., den Brok, M. H., Kramer, M., Bennink, E. J., Toonen, L. W., Kullberg, B. J., Joosten, L. A., Akira, S., Netea, M. G., Adema, G. J. (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells J. Clin. Invest. 116,485-494[CrossRef][Medline]
    9. 9
  9. Hawlisch, H., Belkaid, Y., Baelder, R., Hildeman, D., Gerard, C., Kohl, J. (2005) C5a negatively regulates Toll-like receptor 4-induced immune responses Immunity 22,415-426[CrossRef][Medline]
    10. 10
  10. Grazia Cappiello, M., Sutterwala, F. S., Trinchieri, G., Mosser, D. M., Ma, X. (2001) Suppression of IL-12 transcription in macrophages following Fc {gamma} receptor ligation J. Immunol. 166,4498-4506[Abstract/Free Full Text]
    11. 11
  11. Aliprantis, A. O., Yang, R. B., Mark, M. R., Suggett, S., Devaux, B., Radolf, J. D., Klimpel, G. R., Godowski, P., Zychlinsky, A. (1999) Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2 Science 285,736-739[Abstract/Free Full Text]
    12. 12
  12. Liew, F. Y., Xu, D., Brint, E. K., O’Neill, L. A. (2005) Negative regulation of Toll-like receptor-mediated immune responses Nat. Rev. Immunol. 5,446-458[CrossRef][Medline]
    13. 13
  13. Divanovic, S., Trompette, A., Atabani, S. F., Madan, R., Golenbock, D. T., Visintin, A., Finberg, R. W., Tarakhovsky, A., Vogel, S. N., Belkaid, Y., Kurt-Jones, E. A., Karp, C. L. (2005) Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105 Nat. Immunol. 6,571-578[CrossRef][Medline]
    14. 14
  14. Iwami, K. I., Matsuguchi, T., Masuda, A., Kikuchi, T., Musikacharoen, T., Yoshikai, Y. (2000) Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling J. Immunol. 165,6682-6686[Abstract/Free Full Text]
    15. 15
  15. Mitsuzawa, H., Nishitani, C., Hyakushima, N., Shimizu, T., Sano, H., Matsushima, N., Fukase, K., Kuroki, Y. (2006) Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice J. Immunol. 177,8133-8139[Abstract/Free Full Text]
    16. 16
  16. LeBouder, E., Rey-Nores, J. E., Rushmere, N. K., Grigorov, M., Lawn, S. D., Affolter, M., Griffin, G. E., Ferrara, P., Schiffrin, E. J., Morgan, B. P., Labeta, M. O. (2003) Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk J. Immunol. 171,6680-6689[Abstract/Free Full Text]
    17. 17
  17. Sweet, M. J., Leung, B. P., Kang, D., Sogaard, M., Schulz, K., Trajkovic, V., Campbell, C. C., Xu, D., Liew, F. Y. (2001) A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression J. Immunol. 166,6633-6639[Abstract/Free Full Text]
    18. 18
  18. Wald, D., Qin, J., Zhao, Z., Qian, Y., Naramura, M., Tian, L., Towne, J., Sims, J. E., Stark, G. R., Li, X. (2003) SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling Nat. Immunol. 4,920-927[CrossRef][Medline]
    19. 19
  19. Qin, J., Qian, Y., Yao, J., Grace, C., Li, X. (2005) SIGIRR inhibits interleukin-1 receptor- and Toll-like receptor 4-mediated signaling through different mechanisms J. Biol. Chem. 280,25233-25241[Abstract/Free Full Text]
    20. 20
  20. Diehl, G. E., Yue, H. H., Hsieh, K., Kuang, A. A., Ho, M., Morici, L. A., Lenz, L. L., Cado, D., Riley, L. W., Winoto, A. (2004) TRAIL-R as a negative regulator of innate immune cell responses Immunity 21,877-889[CrossRef][Medline]
    21. 21
  21. Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R. C., Wheeler, M. T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., Ma, A. (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses Nat. Immunol. 5,1052-1060[CrossRef][Medline]
    22. 22
  22. Wullaert, A., Verstrepen, L., Van Huffel, S., Adib-Conquy, M., Cornelis, S., Kreike, M., Haegman, M., El Bakkouri, K., Sanders, M., Verhelst, K., Carpentier, I., Cavaillon, J. M., Heyninck, K., Beyaert, R. (2007) LIND/ABIN-3 is a novel lipopolysaccharide-inducible inhibitor of NF-{kappa}B activation J. Biol. Chem. 282,81-90[Abstract/Free Full Text]
    23. 23
  23. Gilchrist, M., Thorsson, V., Li, B., Rust, A. G., Korb, M., Kennedy, K., Hai, T., Bolouri, H., Aderem, A. (2006) Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4 Nature 441,173-178[CrossRef][Medline]
    24. 24
  24. Wang, Y., Tang, Y., Teng, L., Wu, Y., Zhao, X., Pei, G. (2006) Association of β-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling Nat. Immunol. 7,139-147[CrossRef][Medline]
    25. 25
  25. Shinohara, H., Inoue, A., Toyama-Sorimachi, N., Nagai, Y., Yasuda, T., Suzuki, H., Horai, R., Iwakura, Y., Yamamoto, T., Karasuyama, H., Miyake, K., Yamanashi, Y. (2005) Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling J. Exp. Med. 201,333-339[Abstract/Free Full Text]
    26. 26
  26. Kobayashi, K., Hernandez, L. D., Galan, J. E., Janeway, C. A., Jr, Medzhitov, R., Flavell, R. A. (2002) IRAK-M is a negative regulator of Toll-like receptor signaling Cell 110,191-202[CrossRef][Medline]
    27. 27
  27. Hardy, M. P., O’Neill, L. A. (2004) The murine IRAK2 gene encodes four alternatively spliced isoforms, two of which are inhibitory J. Biol. Chem. 279,27699-27708[Abstract/Free Full Text]
    28. 28
  28. Williams, K. L., Lich, J. D., Duncan, J. A., Reed, W., Rallabhandi, P., Moore, C., Kurtz, S., Coffield, V. M., Accavitti-Loper, M. A., Su, L., Vogel, S. N., Braunstein, M., Ting, J. P. (2005) The CATERPILLER protein Monarch-1 is an antagonist of Toll-like receptor-, tumor necrosis factor {alpha}-, and Mycobacterium tuberculosis-induced pro-inflammatory signals J. Biol. Chem. 280,39914-39924[Abstract/Free Full Text]
    29. 29
  29. Janssens, S., Burns, K., Vercammen, E., Tschopp, J., Beyaert, R. (2003) MyD88S, a splice variant of MyD88, differentially modulates NF-{kappa}B- and AP-1-dependent gene expression FEBS Lett. 548,103-107[CrossRef][Medline]
    30. 30
  30. Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R., Tschopp, J. (2003) Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4 J. Exp. Med. 197,263-268[Abstract/Free Full Text]
    31. 31
  31. Carty, M., Goodbody, R., Schroder, M., Stack, J., Moynagh, P. N., Bowie, A. G. (2006) The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling Nat. Immunol. 7,1074-1081[CrossRef][Medline]
    32. 32
  32. Mansell, A., Smith, R., Doyle, S. L., Gray, P., Fenner, J. E., Crack, P. J., Nicholson, S. E., Hilton, D. J., O’Neill, L. A., Hertzog, P. J. (2006) Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation Nat. Immunol. 7,148-155[CrossRef][Medline]
    33. 33
  33. Chuang, T. H., Ulevitch, R. J. (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors Nat. Immunol. 5,495-502[CrossRef][Medline]
    34. 34
  34. Vogel, S. N., Fitzgerald, K. A., Fenton, M. J. (2003) TLRs: differential adapter utilization by Toll-like receptors mediates TLR-specific patterns of gene expression Mol. Interv. 3,466-477[Abstract/Free Full Text]
    35. 35
  35. Seong, S. Y., Matzinger, P. (2004) Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses Nat. Rev. Immunol. 4,469-478[CrossRef][Medline]
    36. 36
  36. Okamura, Y., Watari, M., Jerud, E. S., Young, D. W., Ishizaka, S. T., Rose, J., Chow, J. C., Strauss, J. F., III (2001) The extra domain A of fibronectin activates Toll-like receptor 4 J. Biol. Chem. 276,10229-10233[Abstract/Free Full Text]
    37. 37
  37. Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., Miyake, K., Freudenberg, M., Galanos, C., Simon, J. C. (2002) Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4 J. Exp. Med. 195,99-111[Abstract/Free Full Text]
    38. 38
  38. Biragyn, A., Ruffini, P. A., Leifer, C. A., Klyushnenkova, E., Shakhov, A., Chertov, O., Shirakawa, A. K., Farber, J. M., Segal, D. M., Oppenheim, J. J., Kwak, L. W. (2002) Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2 Science 298,1025-1029[Abstract/Free Full Text]
    39. 39
  39. Miller, Y. I., Viriyakosol, S., Worrall, D. S., Boullier, A., Butler, S., Witztum, J. L. (2005) Toll-like receptor 4-dependent and independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages Arterioscler. Thromb. Vasc. Biol. 25,1213-1219[Abstract/Free Full Text]
    40. 40
  40. Smiley, S. T., King, J. A., Hancock, W. W. (2001) Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4 J. Immunol. 167,2887-2894[Abstract/Free Full Text]
    41. 41
  41. Yu, M., Wang, H., Ding, A., Golenbock, D. T., Latz, E., Czura, C. J., Fenton, M. J., Tracey, K. J., Yang, H. (2006) HMGB1 signals through Toll-like receptor (TLR) 4 and TLR2 Shock 26,174-179[CrossRef][Medline]
    42. 42
  42. Scheibner, K. A., Lutz, M. A., Boodoo, S., Fenton, M. J., Powell, J. D., Horton, M. R. (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2 J. Immunol. 177,1272-1281[Abstract/Free Full Text]
    43. 43
  43. Tsan, M. F., Gao, B. (2004) Endogenous ligands of Toll-like receptors J. Leukoc. Biol. 76,514-519[Abstract/Free Full Text]
    44. 44
  44. Beutler, B. (2004) Inferences, questions and possibilities in Toll-like receptor signaling Nature 430,257-263[CrossRef][Medline]
    45. 45
  45. Oyama, J., Blais, C., Jr, Liu, X., Pu, M., Kobzik, L., Kelly, R. A., Bourcier, T. (2004) Reduced myocardial ischemia-reperfusion injury in Toll-like receptor 4-deficient mice Circulation 109,784-789[Abstract/Free Full Text]
    46. 46
  46. Kleeberger, S. R., Reddy, S., Zhang, L. Y., Jedlicka, A. E. (2000) Genetic susceptibility to ozone-induced lung hyperpermeability: role of Toll-like receptor 4 Am. J. Respir. Cell Mol. Biol. 22,620-627[Abstract/Free Full Text]
    47. 47
  47. Kleeberger, S. R., Reddy, S. P., Zhang, L. Y., Cho, H. Y., Jedlicka, A. E. (2001) Toll-like receptor 4 mediates ozone-induced murine lung hyperpermeability via inducible nitric oxide synthase Am. J. Physiol. Lung Cell. Mol. Physiol. 280,L326-L333[Abstract/Free Full Text]
    48. 48
  48. Tanga, F. Y., Nutile-McMenemy, N., Deleo, J. A. (2005) The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy Proc. Natl. Acad. Sci. USA 102,5856-5861[Abstract/Free Full Text]
    49. 49
  49. Miyake, K., Yamashita, Y., Hitoshi, Y., Takatsu, K., Kimoto, M. (1994) Murine B cell proliferation and protection from apoptosis with an antibody against a 105-kD molecule: unresponsiveness of X-linked immunodeficient B cells J. Exp. Med. 180,1217-1224[Abstract/Free Full Text]
    50. 50
  50. Miyake, K., Yamashita, Y., Ogata, M., Sudo, T., Kimoto, M. (1995) RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family J. Immunol. 154,3333-3340[Abstract]
    51. 51
  51. Miura, Y., Miyake, K., Yamashita, Y., Shimazu, R., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Inazawa, J., Abe, T., Kimoto, M. (1996) Molecular cloning of a human RP105 homologue and chromosomal localization of the mouse and human RP105 genes (Ly64 and LY64) Genomics 38,299-304[CrossRef][Medline]
    52. 52
  52. Fugier-Vivier, I., de Bouteiller, O., Guret, C., Fossiez, F., Banchereau, J., Mattei, M. G., Ait-Yahia, S., Garcia, E., Lebecque, S., Liu, Y. J. (1997) Molecular cloning of human RP105 Eur. J. Immunol. 27,1824-1827[Medline]
    53. 53
  53. Roshak, A. K., Anderson, K. M., Holmes, S. D., Jonak, Z., Bolognese, B., Terrett, J., Marshall, L. A. (1999) Anti-human RP105 sera induces lymphocyte proliferation J. Leukoc. Biol. 65,43-49[Abstract]
    54. 54
  54. Shimazu, R., Akashi, S., Ogata, H., Nagai, Y., Fukudome, K., Miyake, K., Kimoto, M. (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll- like receptor 4 J. Exp. Med. 189,1777-1782[Abstract/Free Full Text]
    55. 55
  55. Schromm, A. B., Lien, E., Henneke, P., Chow, J. C., Yoshimura, A., Heine, H., Latz, E., Monks, B. G., Schwartz, D. A., Miyake, K., Golenbock, D. T. (2001) Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling J. Exp. Med. 194,79-88[Abstract/Free Full Text]
    56. 56
  56. Re, F., Strominger, J. L. (2003) Separate functional domains of human MD-2 mediate Toll-like receptor 4-binding and lipopolysaccharide responsiveness J. Immunol. 171,5272-5276[Abstract/Free Full Text]
    57. 57
  57. Re, F., Strominger, J. L. (2002) Monomeric recombinant MD-2 binds Toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness J. Biol. Chem. 277,23427-23432[Abstract/Free Full Text]
    58. 58
  58. Miyake, K., Shimazu, R., Kondo, J., Niki, T., Akashi, S., Ogata, H., Yamashita, Y., Miura, Y., Kimoto, M. (1998) Mouse MD-1, a molecule that is physically associated with RP105 and positively regulates its expression J. Immunol. 161,1348-1353[Abstract/Free Full Text]
    59. 59
  59. Miura, Y., Shimazu, R., Miyake, K., Akashi, S., Ogata, H., Yamashita, Y., Narisawa, Y., Kimoto, M. (1998) RP105 is associated with MD-1 and transmits an activation signal in human B cells Blood 92,2815-2822[Abstract/Free Full Text]
    60. 60
  60. Nagai, Y., Shimazu, R., Ogata, H., Akashi, S., Sudo, K., Yamasaki, H., Hayashi, S., Iwakura, Y., Kimoto, M., Miyake, K. (2002) Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide Blood 99,1699-1705[Abstract/Free Full Text]
    61. 61
  61. Yamashita, Y., Miyake, K., Miura, Y., Kaneko, Y., Yagita, H., Suda, T., Nagata, S., Nomura, J., Sakaguchi, N., Kimoto, M. (1996) Activation mediated by RP105 but not CD40 makes normal B cells susceptible to anti-IgM-induced apoptosis: a role for Fc receptor coligation J. Exp. Med. 184,113-120[Abstract/Free Full Text]
    62. 62
  62. Yazawa, N., Fujimoto, M., Sato, S., Miyake, K., Asano, N., Nagai, Y., Takeuchi, O., Takeda, K., Okochi, H., Akira, S., Tedder, T. F., Tamaki, K. (2003) CD19 regulates innate immunity by the Toll-like receptor RP105 signaling in B lymphocytes Blood 102,1374-1380[Abstract/Free Full Text]
    63. 63
  63. Ogata, H., Su, I., Miyake, K., Nagai, Y., Akashi, S., Mecklenbrauker, I., Rajewsky, K., Kimoto, M., Tarakhovsky, A. (2000) The Toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells J. Exp. Med. 192,23-29[Abstract/Free Full Text]
    64. 64
  64. Chan, V. W., Mecklenbrauker, I., Su, I., Texido, G., Leitges, M., Carsetti, R., Lowell, C. A., Rajewsky, K., Miyake, K., Tarakhovsky, A. (1998) The molecular mechanism of B cell activation by Toll-like receptor protein RP-105 J. Exp. Med. 188,93-101[Abstract/Free Full Text]
    65. 65
  65. Nagai, Y., Kobayashi, T., Motoi, Y., Ishiguro, K., Akashi, S., Saitoh, S., Kusumoto, Y., Kaisho, T., Akira, S., Matsumoto, M., Takatsu, K., Miyake, K. (2005) The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes J. Immunol. 174,7043-7049[Abstract/Free Full Text]
    66. 66
  66. Visintin, A., Latz, E., Monks, B. G., Espevik, T., Golenbock, D. T. (2003) Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction J. Biol. Chem. 278,48313-48320[Abstract/Free Full Text]
    67. 67
  67. Tsuneyoshi, N., Fukudome, K., Kohara, J., Tomimasu, R., Gauchat, J. F., Nakatake, H., Kimoto, M. (2005) The functional and structural properties of MD-2 required for lipopolysaccharide binding are absent in MD-1 J. Immunol. 174,340-344[Abstract/Free Full Text]
    68. 68
  68. Nagai, Y., Akashi, S., Nagafuku, M., Ogata, M., Iwakura, Y., Akira, S., Kitamura, T., Kosugi, A., Kimoto, M., Miyake, K. (2002) Essential role of MD-2 in LPS responsiveness and TLR4 distribution Nat. Immunol. 3,667-672[Medline]
    69. 69
  69. Visintin, A., Halmen, K. A., Khan, N., Monks, B. G., Golenbock, D. T., Lien, E. (2006) MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4) J. Leukoc. Biol. 80,1584-1592[Abstract/Free Full Text]
    70. 70
  70. Kropf, P., Freudenberg, M. A., Modolell, M., Price, H. P., Herath, S., Antoniazi, S., Galanos, C., Smith, D. F., Muller, I. (2004) Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major Infect. Immun. 72,1920-1928[Abstract/Free Full Text]
    71. 71
  71. Kropf, P., Freudenberg, N., Kalis, C., Modolell, M., Herath, S., Galanos, C., Freudenberg, M., Muller, I. (2004) Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a role for Toll-like receptor 4 in the control of parasite replication J. Leukoc. Biol. 76,48-57[Abstract/Free Full Text]
    72. 72
  72. Kikuchi, Y., Koarada, S., Tada, Y., Ushiyama, O., Morito, F., Suzuki, N., Ohta, A., Miyake, K., Kimoto, M., Horiuchi, T., Nagasawa, K. (2002) RP105-lacking B cells from lupus patients are responsible for the production of immunoglobulins and autoantibodies Arthritis Rheum. 46,3259-3265[CrossRef][Medline]
    73. 73
  73. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S., Medzhitov, R. (2004) Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis Cell 118,229-241[CrossRef][Medline]
    74. 74
  74. Fukata, M., Michelsen, K. S., Eri, R., Thomas, L. S., Hu, B., Lukasek, K., Nast, C. C., Lechago, J., Xu, R., Naiki, Y., Soliman, A., Arditi, M., Abreu, M. T. (2005) Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis Am. J. Physiol. Gastrointest. Liver Physiol. 288,G1055-G1065[Abstract/Free Full Text]
    75. 75
  75. Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., Prestwich, G. D., Mascarenhas, M. M., Garg, H. G., Quinn, D. A., Homer, R. J., Goldstein, D. R., Bucala, R., Lee, P. J., Medzhitov, R., Noble, P. W. (2005) Regulation of lung injury and repair by Toll-like receptors and hyaluronan Nat. Med. 11,1173-1179[CrossRef][Medline]
    76. 76
  76. Taylor, K. R., Trowbridge, J. M., Rudisill, J. A., Termeer, C. C., Simon, J. C., Gallo, R. L. (2004) Hyaluronan fragments stimulate endothelial recognition of injury through TLR4 J. Biol. Chem. 279,17079-17084[Abstract/Free Full Text]
    77. 77
  77. Gorczynski, R. M., Kai, Y., Miyake, K. (2006) MD1 expression regulates development of regulatory T cells J. Immunol. 177,1078-1084[Abstract/Free Full Text]
    78. 78
  78. Oliver, A. M., Martin, F., Kearney, J. F. (1999) IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells J. Immunol. 162,7198-7207[Abstract/Free Full Text]
    79. 79
  79. Oliver, A. M., Martin, F., Gartland, G. L., Carter, R. H., Kearney, J. F. (1997) Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses Eur. J. Immunol. 27,2366-2374[Medline]
    80. 80
  80. Gunn, K. E., Brewer, J. W. (2006) Evidence that marginal zone B cells possess an enhanced secretory apparatus and exhibit superior secretory activity J. Immunol. 177,3791-3798[Abstract/Free Full Text]
    81. 81
  81. Akashi, S., Shimazu, R., Ogata, H., Nagai, Y., Takeda, K., Kimoto, M., Miyake, K. (2000) Cutting edge: cell surface expression and lipopolysaccharide signaling via the Toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages J. Immunol. 164,3471-3475[Abstract/Free Full Text]
    82. 82
  82. Dziarski, R., Wang, Q., Miyake, K., Kirschning, C. J., Gupta, D. (2001) MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components J. Immunol. 166,1938-1944[Abstract/Free Full Text]



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