Published online before print July 1, 2003
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Department of Immunology, The Scripps Research Institute, La Jolla, California
1Correspondence: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail: bruce{at}scripps.edu
Key Words: lipopolysaccharide • MD-2 molecule • interleukin-1 • TNF • infection • sepsis • adjuvant • interferon • innate immunity
At the same time, vast progress in biology has come from reductionism. The search for the primary cause of events has often led investigators to disrupt individual molecules. This, in turn, has allowed inferences about precisely what is required for a biological system to function as it does. In time, these inferences may accumulate so that every requirement for proper function of a complex system is understood, much as every enzyme in the tricarboxylic acid cycle is now known. In no field has reductionism played a greater role than it has in the science of genetics. Mutations have fueled progress in genetics, and genetic tools have transformed every area of biology.
The present review concerns innate immunity: the inherited resistance to infection, shared to some extent by all normal metazoans. We would like to understand innate immunity at a fine molecular level. We would like to catalog each of the biochemical events that innate immunity entails so that every protein participant in the innate immune response is known. We would like to understand the temporal sequence of molecular interactions that occur and the importance of this temporal sequence to the outcome that is observed. In the long run, we might wish to modify innate immune responses, damping them when they cause harm (as they do in the course of inflammatory diseases) and augmenting them when they are required (as they are during focal infections that need to be checked before they become generalized).
Undoubtedly, the most celebrated of these was lipopolysaccharide (LPS), the principal glycolipid component of the outer membrane of Gram-negative bacteria. The primary structure of LPS was solved during the early 1970s [1 ]. In addition, cord factor (trehalose dimycolate) [2 ], peptidoglycan [3 ], double-stranded RNA [4 ], and unmethylated DNA [5 ] were all shown to induce innate immune responses and to have adjuvant effects as well (see ref. [6 ] for a review).
As LPS could reproduce many of the features of an authentic Gram-negative infection and as it was easy to produce and store, it was widely used as an inducer of immune responses even in the absence of information concerning its receptor. The nature of the LPS sensor, presently believed to have three essential subunits, became clear in three stages. First, CD14 was shown to be essential for LPS responses [7 ]. Second, positional cloning revealed the membrane-spanning component of the receptor [Toll-like receptor 4 (TLR4); refs. 8 , 9 ]. Finally, a small, exteriorized molecule known as MD-2 was shown to be an essential part of the receptor complex [10 , 11 ]. The existence of still other components cannot, at this point, be excluded [12 ].
The signaling domain of each of the TLRs [the so-called TIR domain, denoting TLRs, interleukin-1 receptors (IL-1Rs), and plant disease-resistance genes] had some years earlier been recognized as an immunologically important motif. In Drosophila, Toll was shown to be required for defense against fungal infection [24
]; in mammals, IL-1 and IL-18 were known to be involved in innate and adaptive immune responses [25
]. IL-1 [26
] and Toll [27
28
29
] were known to signal through activation of nuclear factor-
B (NF-B), and subsequently, soon after its identification, it was shown that TLR4 could do so as well [15
].
Toll of Drosophila does not directly engage microbial ligands but rather a protein ligand (Spaetzle) [30 ]. However, the mammalian TLRs apparently do. Genetic [31 , 32 ] and biochemical [33 ] evidence of interaction between LPS and TLR4 has been presented. LPS is first engaged by CD14 and then brought into direct contact with TLR4 and MD-2 [11 , 34 ]. By implication, other TLRs may also bind microbial inducer molecules, as discussed below. Indeed, the case has been established for TLR9 with regard to DNA binding [35 ] and for TLR2 with regard to peptidoglycan binding [36 ] using methods similar to those used for TLR4. However, the TLRs may require accessory proteins for ligand presentation, and some genetic evidence suggests that this is the case.
The discovery that TLR4 signals the presence of LPS—and the strong likelihood that it exists exclusively for this purpose—made it seem probable that the other TLRs could each signal the presence of other microbial inducers. In this manner, much of the microbial world might be recognized by a handful of innate immune receptors. A combination of reverse genetic methods was used to demonstrate that this was the case. Underhill et al. [37 ] applied a dominant-negative approach to implicate TLR2 as the receptor for molecules of Gram-positive origin, an impression substantiated by the discovery that knockout of TLR2 made mouse macrophages refractory to activation by peptidoglycan and bacterial lipopeptides [38 ]. Later, TLR1 and -6 were shown to engage in heteromer formation with TLR2 [39 ], each contributing to a different specificity of recognition [40 ]. TLR5 was shown to recognize flagellin [41 ], a conclusion based on the effects of mutations in bacteria rather than mutations in the host (i.e., bacterial strains that lack flagellin fail to induce a response in cells transfected to express TLR5). TLR9 and -3 were shown to identify unmethylated DNA and double-stranded RNA, respectively [42 , 43 ]. Finally, although an authentic microbial product has not yet been identified for TLR7, small, antiviral molecules with a nucleoside structure (imiquimod and resiquimod) were shown to stimulate cells via TLR7 [44 ]. In humans, it is believed that TLR8 may also act as a receptor for these ligands [45 ].
Although a large number of other molecules have been offered as putative TLR ligands as well, a conservative view of the specificities is presented in Figure 1 . In the case of TLR4 itself, many other agonists have been proposed, including endogenous and virally encoded proteins. However, most have not yet been substantiated in systems that would entirely exclude the possible action of LPS, and at present, only LPS and taxol (the latter being an agonist for mouse TLR4 but not human TLR4) are accepted as proven ligands by the authors of this review.
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Figure 1. The human TLRs and their specific ligands. Leucine-rich repeat (LRR) motifs are scattered throughout the ectodomains and are depicted as green rectangles; membrane-proximal LRRs have a different structure and are shown in pink. Green ovals represent TIR domains, the most conserved part of each of the receptors. TLR10 is a pseudogene in mice, which have two additional TLRs (not illustrated here) that are pseudogenes in humans. TLR1 and -2 and TLR-6 and -2 are known to form heterodimers. PG, peptidoglycan; LP, bacterial lipopeptides; zym, zymosan; GPI, glycosylphosphoinositol; IMQ, imiquimod; RSQ, resiquimod; 848, another congener of imiquimod and resiquimod; CpG, unmethyated DNA with immunostimulatory CpG dinucleotide-containing sequences.
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The discovery of the TLRs as primary sensors of microbial infection was also a landmark advance, as the TLRs are the most proximal host initiators of septic shock and for that matter, most of the responses that infectious organisms provoke. The TLRs stand at the top of the innate immune response cascade, crossing the membrane of host responder cells. They are the most important interface between mammalian host and microbe. Without them, there would be very little in the way of awareness that infection had occurred.
Just as they precipitate the "bad" effects of infection, it is clear that the TLRs protect against infection. Since the 1980s, the Lps mutation (now known to reside within the TLR4 gene) has been known to cause impaired responses to Gram-negative bacterial infection by entirely preventing host recognition of LPS [47 ]. Hence, Gram-negative bacteria may overwhelm the host by stealth. A small, Gram-negative inoculum, normally containable, may gain a foothold in an animal "blind" to endotoxin.
It is difficult to catalog the end effects of TLR activation, as these effects are so numerous, and one comes to a blanket description of inflammation itself. The intended effects (untoward if excessive or generalized) include recruitment of leukocytes, activation of microbicidal activity (i.e., the production of oxygen radicals, antimicrobial peptides, and hydrolytic enzymes), the relaxation of blood vessels mediated by nitric oxide (NO) and by autacoids, and abetment of the adaptive immune response (i.e., an adjuvant effect). Conversely, as a distinct biochemical cascade, which is initiated by receptor activation itself, elicited each of these end processes, much attention has been devoted to the proximal events that follow TLR stimulation.
The MyD88-dependent pathway entails recruitment of IL-1R-associated kinase (IRAK) isoforms (IRAK4 being particularly important [52
]), tumor necrosis factor (TNF) receptor-associated factor-6 (TRAF-6) [53
, 54
], and transforming growth factor-ß-activated kinase-1 (TAK-1) [55
] and activation of the signalosome, with subsequent translocation of NF-B to the nucleus and the transcriptional activation of numerous cytokine genes.
The MyD88-independent pathway leads to the activation of the interferon-ß (IFN-ß) gene [48 , 56 ], and presumably other genes dependent on IFN regulatory factor-3 (IRF-3) activation. Type I IFNs, acting through their own receptors, activate the Janus kinases, which in turn, phosphorylate signal transducer and activator of transcription (STAT) proteins, leading to the transcriptional activation of other genes, including many that are required for effective antiviral defense and other genes encoding proteins involved in the inflammatory response, such as the IFN-inducible protein 10 (IP-10) gene and the inducible NO synthase (iNOS) gene [56 ].
In the case of TLR4, association with at least three TIR domain-containing proteins occurs. The first of these, discussed above, is MyD88. However, in addition, MyD88 adapter-like [MAL; also known as Toll/IL-1R domain-containing adapter protein (Tirap); refs. 57 , 58 ] and TIR domain-containing adapter-inducing IFN-ß (Trif) [59 , 60 ] recruitment also takes place. Targeted deletion of the MAL/Tirap gene yields a phenotype similar to that observed with MyD88 deletion, affecting not only the TLR4 receptor complex but also the TLR2 receptor [61 , 62 ]. Trif mutants have not yet been generated, but it is likely that the Trif protein serves a MyD88-independent pathway of response (Fig. 2 ). Trif binds to numerous TLRs, as well as to IRF-3, and dominant-negative mutants of Trif seem to block signaling via IRF-3, preventing the production of IFN-ß [59 ].
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Figure 2. The principal pathways of LPS signal transduction. MyD88-dependent signaling (left) depends on MyD88 and MAL/Tirap. MyD88-independent signaling (right) is clearly known from forward genetic studies to be dependent on the product of a gene known as Lps2 and on the basis of transfection studies, may also depend on Trif, one of five adaptor proteins known to be present in the human and mouse genomes. Both pathways may activate NF-B and the mitogen-activated protein kinase (MAPK) cascade. Only the MyD88-independent pathway activates IFN-ß production. IKK, IB kinase; PI-3K, phosphatidylinositol-3 kinase; MIP-1 , macrophage-inflammatory protein-1.
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The "forward genetic" approach holds that all genes required for a particular biological function can be identified by finding mutations that disrupt the function in question. The forward genetic approach is driven by phenotype. Rather than beginning with a protein, one begins with functional alteration and then searches for a mutation that explains this alteration.
Forward genetic approaches (e.g., the identification of Lps as TLR4) and reverse genetic approaches (e.g., the knockout of the TLRs and TIR domain proteins accomplished to date) have been used to decipher the mechanisms of innate immune sensing. Each method opens the door to other approaches. For example, a systematic search for TIR domain proteins led to the identification of Trif and MAL/Tirap, and biochemical assessments of molecular interactions have disclosed the participation of other proteins, such as MD-2, in signal transduction.
As a generalization, forward genetic methods can yield real surprises and as it makes no prejudgments about function, can open entirely new fields for study. Molecules with no known function or molecules with functions that were not thought to be related to a particular phenomenon at all can be shown to be essential for that phenomenon to occur. A shortage of phenotypes limits the practice of forward genetic analysis. Where interstrain phenotypic differences exist, they often have a polygenic basis and are therefore difficult to clone. Monogenic phenotypes are therefore the most interesting and important to follow. To create monogenic phenotype, germline mutagenesis is often used, and the mutagen of choice is N-ethyl-N-nitrosourea.
Several germline mutations that impair innate immune sensing have been identified during the past few months. These include Lps2, a codominant mutation that prevents LPS [12 ] and poly I:C (K. Hoebe et al., submitted) sensing; Panr1, a mutation that blocks all signaling initiated by microbial inducers (K. Hoebe et al., unpublished); and Pgn1, a mutation that selectively impedes responses to peptidoglycan (but has no effect on signaling by other TLR2 agonists; K. Hoebe et al., submitted). The functional position of each of these mutations is shown in Figure 3 .
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Figure 3. Illustration of the principal signaling pathways activated by TLRs. Gram-negative and Gram-positive bacteria and perhaps viruses (red shapes) produce molecules that activate different TLRs or TLR complexes (blue), which in turn, impinge on a collection of transducer molecules. It is clear that TLR4, the LPS receptor, requires MyD88, MAL/Tirap, and other transducer molecules yet to be assigned. TLR2 requires only MyD88 and MAL/Tirap for signaling, so far as is known. TLR3 is perhaps somewhat dependent on MyD88 but also on other transducers. The integration of signals leads, in the case of the LPS response, to activation of the MyD88-dependent and MyD88-independent signaling pathways. TLR3 perhaps activates the MyD88-independent pathway exclusively. This pathway includes, among its many endpoints, the induction of IFN-ß synthesis and all downstream events that follow STAT activation. Flux through the pathway is also required for effective TNF production. Among the principal endpoints of the MyD88-dependent pathway is NF-B activation, on which TNF production also depends. TNF, a hallmark of LPS activation and one of the principal mediators of LPS toxicity, initiates two separate signaling pathways of its own (right). Forward genetic methods have been used to detect essential components of this pathway (yellow ovals). LBP, LPS-binding protein; PGN, peptidoglycan; LP, lipoprotein; FADD, Fas-associated death domain; TRADD, TNFR-associated death domain; RIP, receptor-interacting protein; MEKK, MAPK kinase kinase. Flg, flagellin. PanRI, "Pan-resistance I," a mutation known to block TNF production in response to all stimuli.
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Why is there so much overlap, and what accounts for the specificity that can be detected? In part, there is commonality of signal transducers. MAL/Tirap apparently serves TLR2 and TLR4 but not other TLRs. The specificity of Trif is not yet known with certainty: It has been claimed to serve TLR3 alone [60 ] or alternatively, several of the TLRs [59 ]. MyD88 is believed to be universal (i.e., nonspecific) and is required for signaling from the IL-1 and IL-18 receptors as well as the TLRs [65 ]. From germline mutagenesis studies, it appears that the protein encoded by Lps2 serves only TLR3 and -4 [12 ].
There are 10 human TLRs and only three known transducers. It has also been shown that at least in some cases, TLRs engage in heteromer formation, broadening the specificity of molecules that are recognized. For example, TLR2 can combine with TLR1 or TLR6 and is likely to also exist as a homodimer [39 ]. It might therefore be expected that the informational potential of the receptors is lost in the course of signaling, as once a transducer is activated, the cell can no longer "know" which receptor was responsible. However, the ratio of activation of different transducers, the temporal relationship between activation of different transducers, and the subcellular location of the receptors and transducers might be influential in directing the output of the response. Therefore, although TLR2 and TLR4 might recruit MyD88, MAL/Tirap, and Trif, the ligands for these receptors do not yield identical responses. Furthermore, although TLR7, -8, and -9 are believed to reside within the cytoplasm of responding cells, perhaps anchored within the endosomes, TLR4 is at least partly located at the cell surface.
Beyond this, it is entirely possible that many of the proteins that serve the TLRs have yet to be identified. Some may indeed be entirely unique to particular receptors.
B [14
]. It has been widely suggested that the TLRs are important in adaptive immunity, as they are in innate immunity. In fact, this is the case, although adaptive immune responses occur far downstream from TLR activation. Although it is sometimes presented as a new concept, the dependence of adaptive immunity on cells of the innate immune system has been known for a very long time. The vital antigen-presenting role of innate immune cells accounts for much of this dependency. The assistance rendered by specific host molecules such as IL-1, CD40L, class II major histocompatibility complex antigens, and B7 antigens, each of which is produced or up-regulated in response to LPS or other microbial stimuli, was established decades ago. The adjuvant effect of molecules of microbial origin was evident earlier still (for a review, see ref. [6 ]).
An attractive hypothesis concerning the role played by TLRs in the activation of adaptive immunity holds that the precise combination of TLRs activated by a given microbial infection leads to "tailoring" the adaptive immune response so that it can deal with that specific infection. Hence, a DC, stimulated by LPS, might direct the development of an adaptive response that is better suited for dealing with Gram-negative organisms than Gram-positive organisms. However, if true, this notion would be very difficult to prove, given the formal similarities of the adaptive response to all organisms.
Certain corollaries to the hypothesis that TLRs are critically important to the development of adaptive immune responses, although often cited, are difficult to sustain in the face of existing information about the immune response. One of these corollaries is the notion that self-tolerance prevails because of a lack of TLR signaling and hence, the lack of a costimulus in the form of CD80 [66 ]. However, the administration of a TLR agonist (or the introduction of an infectious agent) does not, by itself, break tolerance to the normal tissues of the host nor to tissues that have been damaged or destroyed as a result of the infectious process.
A second corollary holds that TLR activation provides an essential "second signal" for an adaptive immune response [67 ]. Although as adjuvants of all kinds enhance the adaptive immune response by definition, they are not essential for its occurrence. Immune responses to allografts, for example, can be exceptionally strong and occur in the absence of any TLR agonist. Immune responses to many viruses undoubtedly also circumvent the TLR-sensing system. Isolated foreign proteins are, of course, immunogenic as well, whether they are introduced as highly purified preparations in the absence of adjuvants or are made by recombinant means within the host (e.g., when encoded by a viral vector).
The element of timing is crucial to innate immune responses and to the determination of whether harm or good will come of them. Innate immune responses are not elicited all at once but in an optimal sequence. Such is the complexity of innate immunity that success in understanding it will hinge on the integration of systems biology and reductionism with all the tools that each can apply.
Received February 24, 2003; revised April 17, 2003; accepted April 18, 2003.
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S. Totemeyer, M. Sheppard, A. Lloyd, D. Roper, C. Dowson, D. Underhill, P. Murray, D. Maskell, and C. Bryant IFN-{gamma} Enhances Production of Nitric Oxide from Macrophages via a Mechanism That Depends on Nucleotide Oligomerization Domain-2. J. Immunol., April 15, 2006; 176(8): 4804 - 4810. [Abstract] [Full Text] [PDF]
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B. Salaun, I. Coste, M.-C. Rissoan, S. J. Lebecque, and T. Renno TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells. J. Immunol., April 15, 2006; 176(8): 4894 - 4901. [Abstract] [Full Text] [PDF]
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Q. Pan, V. Kravchenko, A. Katz, S. Huang, M. Ii, J. C. Mathison, K. Kobayashi, R. A. Flavell, R. D. Schreiber, D. Goeddel, et al. NF-{kappa}B-Inducing Kinase Regulates Selected Gene Expression in the Nod2 Signaling Pathway Infect. Immun., April 1, 2006; 74(4): 2121 - 2127. [Abstract] [Full Text] [PDF]
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 S.J. Challacombe and J.R. Naglik The Effects of HIV Infection on Oral Mucosal Immunity Advances in Dental Research, April 1, 2006; 19(1): 29 - 35. [Abstract] [Full Text] [PDF]
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 L. M. Kreckler, T. C. Wan, Z.-D. Ge, and J. A. Auchampach Adenosine Inhibits Tumor Necrosis Factor-{alpha} Release from Mouse Peritoneal Macrophages via A2A and A2B but Not the A3 Adenosine Receptor J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 172 - 180. [Abstract] [Full Text] [PDF]
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 E. L. Cooper Role of TOLL-like Receptors in Adjuvant-Augmented Immune Therapies by T. Seya. Evid. Based Complement. Altern. Med., March 1, 2006; 3(1): 133 - 137. [Full Text] [PDF]
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M. Muthukuru and C. W. Cutler Upregulation of Immunoregulatory Src Homology 2 Molecule Containing Inositol Phosphatase and Mononuclear Cell Hyporesponsiveness in Oral Mucosa during Chronic Periodontitis Infect. Immun., February 1, 2006; 74(2): 1431 - 1435. [Abstract] [Full Text] [PDF]
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C. C. Tydell, J. Yuan, P. Tran, and M. E. Selsted Bovine Peptidoglycan Recognition Protein-S: Antimicrobial Activity, Localization, Secretion, and Binding Properties J. Immunol., January 15, 2006; 176(2): 1154 - 1162. [Abstract] [Full Text] [PDF]
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W. Vermi, F. Facchetti, E. Riboldi, H. Heine, S. Scutera, S. Stornello, D. Ravarino, P. Cappello, M. Giovarelli, R. Badolato, et al. Role of dendritic cell-derived CXCL13 in the pathogenesis of Bartonella henselae B-rich granuloma Blood, January 15, 2006; 107(2): 454 - 462. [Abstract] [Full Text] [PDF]
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R. M. Newman, P. Salunkhe, A. Godzik, and J. C. Reed Identification and Characterization of a Novel Bacterial Virulence Factor That Shares Homology with Mammalian Toll/Interleukin-1 Receptor Family Proteins Infect. Immun., January 1, 2006; 74(1): 594 - 601. [Abstract] [Full Text] [PDF]
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 S. Herath, D. P. Fischer, D. Werling, E. J. Williams, S. T. Lilly, H. Dobson, C. E. Bryant, and I. M. Sheldon Expression and Function of Toll-Like Receptor 4 in the Endometrial Cells of the Uterus Endocrinology, January 1, 2006; 147(1): 562 - 570. [Abstract] [Full Text] [PDF]
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A. V. Grishin, J. Wang, D. A. Potoka, D. J. Hackam, J. S. Upperman, P. Boyle, R. Zamora, and H. R. Ford Lipopolysaccharide Induces Cyclooxygenase-2 in Intestinal Epithelium via a Noncanonical p38 MAPK Pathway J. Immunol., January 1, 2006; 176(1): 580 - 588. [Abstract] [Full Text] [PDF]
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S. Knapp, C. W. Wieland, S. Florquin, R. Pantophlet, L. Dijkshoorn, N. Tshimbalanga, S. Akira, and T. van der Poll Differential Roles of CD14 and Toll-like Receptors 4and 2 in Murine Acinetobacter Pneumonia Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 122 - 129. [Abstract] [Full Text] [PDF]
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P. B. Mann, D. Wolfe, E. Latz, D. Golenbock, A. Preston, and E. T. Harvill Comparative Toll-Like Receptor 4-Mediated Innate Host Defense to Bordetella Infection Infect. Immun., December 1, 2005; 73(12): 8144 - 8152. [Abstract] [Full Text] [PDF]
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G. S. Kirimanjeswara, P. B. Mann, M. Pilione, M. J. Kennett, and E. T. Harvill The Complex Mechanism of Antibody-Mediated Clearance of Bordetella from the Lungs Requires TLR4 J. Immunol., December 1, 2005; 175(11): 7504 - 7511. [Abstract] [Full Text] [PDF]
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S. Kumar, A. Roychowdhury, B. Ember, Q. Wang, R. Guan, R. A. Mariuzza, and G.-J. Boons Selective Recognition of Synthetic Lysine and meso-Diaminopimelic Acid-type Peptidoglycan Fragments by Human Peptidoglycan Recognition Proteins I{alpha} and S J. Biol. Chem., November 4, 2005; 280(44): 37005 - 37012. [Abstract] [Full Text] [PDF]
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M. A. Hughes, C. S. Green, L. Lowchyj, G. M. Lee, V. K. Grippe, M. F. Smith Jr., L.-Y. Huang, E. T. Harvill, and T. J. Merkel MyD88-Dependent Signaling Contributes to Protection following Bacillus anthracis Spore Challenge of Mice: Implications for Toll-Like Receptor Signaling Infect. Immun., November 1, 2005; 73(11): 7535 - 7540. [Abstract] [Full Text] [PDF]
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J. S. Hadley, J. E. Wang, S. J. Foster, C. Thiemermann, and C. J. Hinds Peptidoglycan of Staphylococcus aureus Upregulates Monocyte Expression of CD14, Toll-Like Receptor 2 (TLR2), and TLR4 in Human Blood: Possible Implications for Priming of Lipopolysaccharide Signaling Infect. Immun., November 1, 2005; 73(11): 7613 - 7619. [Abstract] [Full Text] [PDF]
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O. Pino, M. Martin, and S. M. Michalek Cellular Mechanisms of the Adjuvant Activity of the Flagellin Component FljB of Salmonella enterica Serovar Typhimurium To Potentiate Mucosal and Systemic Responses Infect. Immun., October 1, 2005; 73(10): 6763 - 6770. [Abstract] [Full Text] [PDF]
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K. B. Goralski, D. Abdulla, C. J. Sinal, A. Arsenault, and K. W. Renton Toll-like receptor-4 regulation of hepatic Cyp3a11 metabolism in a mouse model of LPS-induced CNS inflammation Am J Physiol Gastrointest Liver Physiol, September 1, 2005; 289(3): G434 - G443. [Abstract] [Full Text] [PDF]
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M. B. Hinckley, C. M. Reynolds, A. A. Ribeiro, S. C. McGrath, R. J. Cotter, F. N. Lauw, D. T. Golenbock, and C. R. H. Raetz A Leptospira interrogans Enzyme with Similarity to Yeast Ste14p That Methylates the 1-Phosphate Group of Lipid A J. Biol. Chem., August 26, 2005; 280(34): 30214 - 30224. [Abstract] [Full Text] [PDF]
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M. M. Wurfel, W. Y. Park, F. Radella, J. Ruzinski, A. Sandstrom, J. Strout, R. E. Bumgarner, and T. R. Martin Identification of High and Low Responders to Lipopolysaccharide in Normal Subjects: An Unbiased Approach to Identify Modulators of Innate Immunity J. Immunol., August 15, 2005; 175(4): 2570 - 2578. [Abstract] [Full Text] [PDF]
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Z. Orinska, E. Bulanova, V. Budagian, M. Metz, M. Maurer, and S. Bulfone-Paus TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment Blood, August 1, 2005; 106(3): 978 - 987. [Abstract] [Full Text] [PDF]
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C. Chan, L. Li, C. E. McCall, and B. K. Yoza Endotoxin Tolerance Disrupts Chromatin Remodeling and NF-{kappa}B Transactivation at the IL-1{beta} Promoter J. Immunol., July 1, 2005; 175(1): 461 - 468. [Abstract] [Full Text] [PDF]
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 Y. C. Luiking, M. M. Hallemeesch, W. H. Lamers, and N. E. P. Deutz NOS3 is involved in the increased protein and arginine metabolic response in muscle during early endotoxemia in mice Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1258 - E1264. [Abstract] [Full Text] [PDF]
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S. M. Zughaier, S. M. Zimmer, A. Datta, R. W. Carlson, and D. S. Stephens Differential Induction of the Toll-Like Receptor 4-MyD88-Dependent and -Independent Signaling Pathways by Endotoxins Infect. Immun., May 1, 2005; 73(5): 2940 - 2950. [Abstract] [Full Text] [PDF]
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O. E. Sorensen, D. R. Thapa, A. Rosenthal, L. Liu, A. A. Roberts, and T. Ganz Differential Regulation of {beta}-Defensin Expression in Human Skin by Microbial Stimuli J. Immunol., April 15, 2005; 174(8): 4870 - 4879. [Abstract] [Full Text] [PDF]
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W. J. Kaiser and M. K. Offermann Apoptosis Induced by the Toll-Like Receptor Adaptor TRIF Is Dependent on Its Receptor Interacting Protein Homotypic Interaction Motif J. Immunol., April 15, 2005; 174(8): 4942 - 4952. [Abstract] [Full Text] [PDF]
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M. L. Peterson, K. Ault, M. J. Kremer, A. J. Klingelhutz, C. C. Davis, C. A. Squier, and P. M. Schlievert The Innate Immune System Is Activated by Stimulation of Vaginal Epithelial Cells with Staphylococcus aureus and Toxic Shock Syndrome Toxin 1 Infect. Immun., April 1, 2005; 73(4): 2164 - 2174. [Abstract] [Full Text] [PDF]
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C. Kalis, M. Gumenscheimer, N. Freudenberg, S. Tchaptchet, G. Fejer, A. Heit, S. Akira, C. Galanos, and M. A. Freudenberg Requirement for TLR9 in the Immunomodulatory Activity of Propionibacterium acnes J. Immunol., April 1, 2005; 174(7): 4295 - 4300. [Abstract] [Full Text] [PDF]
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R. Jimenez, E. Belcher, S. Sriskandan, R. Lucas, S. McMaster, I. Vojnovic, T. D. Warner, and J. A. Mitchell Role of Toll-like receptors 2 and 4 in the induction of cyclooxygenase-2 in vascular smooth muscle PNAS, March 22, 2005; 102(12): 4637 - 4642. [Abstract] [Full Text] [PDF]
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D. De Nardo, P. Masendycz, S. Ho, M. Cross, A. J. Fleetwood, E. C. Reynolds, J. A. Hamilton, and G. M. Scholz A Central Role for the Hsp90{middle dot}Cdc37 Molecular Chaperone Module in Interleukin-1 Receptor-associated-kinase-dependent Signaling by Toll-like Receptors J. Biol. Chem., March 18, 2005; 280(11): 9813 - 9822. [Abstract] [Full Text] [PDF]
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A. Sassi, B. Largueche-Darwaz, A. Collette, A. Six, D. Laouini, P. A. Cazenave, and K. Dellagi Mechanisms of the Natural Reactivity of Lymphocytes from Noninfected Individuals to Membrane-Associated Leishmania infantum Antigens J. Immunol., March 15, 2005; 174(6): 3598 - 3607. [Abstract] [Full Text] [PDF]
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K. Vakharia and J. P. Hinson Lipopolysaccharide Directly Stimulates Cortisol Secretion by Human Adrenal Cells by a Cyclooxygenase-Dependent Mechanism Endocrinology, March 1, 2005; 146(3): 1398 - 1402. [Abstract] [Full Text] [PDF]
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 K. Singbartl, S. G.{b.}e Bockhorn, A. Zarbock, M. Schmolke, and H. Van Aken T Cells Modulate Neutrophil-Dependent Acute Renal Failure during Endotoxemia: Critical Role for CD28 J. Am. Soc. Nephrol., March 1, 2005; 16(3): 720 - 728. [Abstract] [Full Text] [PDF]
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M. Muthukuru, R. Jotwani, and C. W. Cutler Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis Infect. Immun., February 1, 2005; 73(2): 687 - 694. [Abstract] [Full Text] [PDF]
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J. R. Schurr, E. Young, P. Byrne, C. Steele, J. E. Shellito, and J. K. Kolls Central Role of Toll-Like Receptor 4 Signaling and Host Defense in Experimental Pneumonia Caused by Gram-Negative Bacteria Infect. Immun., January 1, 2005; 73(1): 532 - 545. [Abstract] [Full Text] [PDF]
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T. Syrovets, B. Buchele, C. Krauss, Y. Laumonnier, and T. Simmet Acetyl-Boswellic Acids Inhibit Lipopolysaccharide-Mediated TNF-{alpha} Induction in Monocytes by Direct Interaction with I{kappa}B Kinases J. Immunol., January 1, 2005; 174(1): 498 - 506. [Abstract] [Full Text] [PDF]
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F. Re and J. L. Strominger IL-10 Released by Concomitant TLR2 Stimulation Blocks the Induction of a Subset of Th1 Cytokines That Are Specifically Induced by TLR4 or TLR3 in Human Dendritic Cells J. Immunol., December 15, 2004; 173(12): 7548 - 7555. [Abstract] [Full Text] [PDF]
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Y. Huang, T. Li, D. C. Sane, and L. Li IRAK1 Serves as a Novel Regulator Essential for Lipopolysaccharide-induced Interleukin-10 Gene Expression J. Biol. Chem., December 3, 2004; 279(49): 51697 - 51703. [Abstract] [Full Text] [PDF]
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 I. Glezer and S. Rivest Glucocorticoids: Protectors of the Brain during Innate Immune Responses Neuroscientist, December 1, 2004; 10(6): 538 - 552. [Abstract] [PDF]
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P. B. Mann, K. D. Elder, M. J. Kennett, and E. T. Harvill Toll-Like Receptor 4-Dependent Early Elicited Tumor Necrosis Factor Alpha Expression Is Critical for Innate Host Defense against Bordetella bronchiseptica Infect. Immun., November 1, 2004; 72(11): 6650 - 6658. [Abstract] [Full Text] [PDF]
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 N. P. Turrin and S. Rivest Unraveling the Molecular Details Involved in the Intimate Link between the Immune and Neuroendocrine Systems Experimental Biology and Medicine, November 1, 2004; 229(10): 996 - 1006. [Abstract] [Full Text] [PDF]
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W. T. Doerrler, H. S. Gibbons, and C. R. H. Raetz MsbA-dependent Translocation of Lipids across the Inner Membrane of Escherichia coli J. Biol. Chem., October 22, 2004; 279(43): 45102 - 45109. [Abstract] [Full Text] [PDF]
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K. Ruckdeschel, G. Pfaffinger, R. Haase, A. Sing, H. Weighardt, G. Hacker, B. Holzmann, and J. Heesemann Signaling of Apoptosis through TLRs Critically Involves Toll/IL-1 Receptor Domain-Containing Adapter Inducing IFN-{beta}, but Not MyD88, in Bacteria-Infected Murine Macrophages J. Immunol., September 1, 2004; 173(5): 3320 - 3328. [Abstract] [Full Text] [PDF]
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C. C. N. Wu, J. Lee, E. Raz, M. Corr, and D. A. Carson Necessity of Oligonucleotide Aggregation for Toll-like Receptor 9 Activation J. Biol. Chem., August 6, 2004; 279(32): 33071 - 33078. [Abstract] [Full Text] [PDF]
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D. E. Spaner Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells J. Leukoc. Biol., August 1, 2004; 76(2): 338 - 351. [Abstract] [Full Text] [PDF]
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 S.-M. Lin, C. W. Frevert, O. Kajikawa, M. M. Wurfel, K. Ballman, S. Mongovin, V. A. Wong, A. Selk, and T. R. Martin Differential Regulation of Membrane CD14 Expression and Endotoxin-Tolerance in Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 162 - 170. [Abstract] [Full Text] [PDF]
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A. Punturieri, R. S. Alviani, T. Polak, P. Copper, J. Sonstein, and J. L. Curtis Specific Engagement of TLR4 or TLR3 Does Not Lead to IFN-{beta}-Mediated Innate Signal Amplification and STAT1 Phosphorylation in Resident Murine Alveolar Macrophages J. Immunol., July 15, 2004; 173(2): 1033 - 1042. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, M. Schito, D. Chaussabel, and A. Sher Influence of Coinfecting Pathogens on HIV Expression: Evidence for a Role of Toll-Like Receptors J. Immunol., June 15, 2004; 172(12): 7229 - 7234. [Abstract] [Full Text] [PDF]
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S. Cetin, H. R. Ford, L. R. Sysko, C. Agarwal, J. Wang, M. D. Neal, C. Baty, G. Apodaca, and D. J. Hackam Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions J. Biol. Chem., June 4, 2004; 279(23): 24592 - 24600. [Abstract] [Full Text] [PDF]
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E. L. Cooper Commentary on CAM and NK Cells by Kazuyoshi Takeda and Ko Okumura Evid. Based Complement. Altern. Med., June 1, 2004; 1(1): 29 - 34. [Full Text] [PDF]
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TOP
ABSTRACT
INTRODUCTION