Department of Molecular Biology, Genentech Inc., South San Francisco, California
Correspondence: Austin L. Gurney, Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080-4990. E-mail: nico{at}gene.com
 TOP ABSTRACT DISCOVERY OF THE INTERLEUKIN-17...BIOLOGICAL ACTIONS OF IL-17...STRUCTURE OF THE IL-17sIL-17RIL-17 SIGNALINGIL-17 IN DISEASECONCLUSIONREFERENCES |
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Key Words: GM-CSF • TNF-
• MAPK • JNK • pathogen
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TOPABSTRACTDISCOVERY OF THE INTERLEUKIN-17...BIOLOGICAL ACTIONS OF IL-17...STRUCTURE OF THE IL-17sIL-17RIL-17 SIGNALINGIL-17 IN DISEASECONCLUSIONREFERENCES |
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The recent large-scale sequencing of expressed sequence tags (est) and genomes of several vertebrate species has led to the identification of additional genes that bear clear homology to IL-17 and thus define an emerging cytokine family [5 6 7 8 9 ]. There are at least six members of the family in the human genome (Fig. 1 ). IL-17B and IL-17C were identified based on est, and a fourth member, as yet unpublished but provisionally termed IL-17D, is also relatively abundantly represented in est databases (unpublished results). A fifth member of the IL-17 family, IL-17E, was first discovered in human genomic sequence [6 ]. The sixth known member of the family, IL-17F, is located adjacent to IL-17 in human genomic sequence [8 ]. Comparison of the human IL-17s with other species suggests that IL-17 family members are highly conserved across vertebrate evolution. In contrast, clear orthologs have not been identified in Drosophila or Caenorhabditis elegans. The IL-17s are all similarly sized, secreted proteins of 150–180 amino acids. They bear greatest similarity within the C-terminal 70 amino acids. Although there is not a strict conservation of spacing, there are four well-conserved cysteines and at least two additional cysteines that appear likely to be functionally conserved but with more variable spacing. Members of the IL-17 family are all expressed as dimers, and with the exception of IL-17B, they are covalent dimers (unpublished results). Recent structural analysis has revealed the unexpected finding that IL-17F and, therefore likely, the other IL-17s adopt a cysteine knot conformation [8 ].
 View larger version (73K): [in a new window] |
Figure 1. Sequence of IL-17 family members. Shown is a sequence alignment of the
six known human IL-17 family members. Identical residues are boxed, and
conserved cysteines are indicated by bullets.
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[15
],
thereby promoting the recruitment of monocytes and neutrophils
[16
17
18
]. Further, it stimulates the production of the
hematopoietic cytokines G-CSF and granulocyte macrophage (GM)-CSF that
promote the expansion of these myeloid lineages
[19
20
21
]. Other actions such as the stimulation of IL-6
and PGE2 production enhance the local inflammatory environment
[4
, 22
23
24
]. In addition, IL-17 also drives
T-cell responses, notably through the induction of the costimulatory
molecule intercellular adhesion molecule (ICAM)
[25
26
27
].
IL-17 has long been considered a molecule produced by activated memory
T cells [1
]. Studies designed to establish whether IL-17
could be classified according to the Th1/Th2 paradigm have been unable
to provide clear categorization [28
29
30
]. Although
individual T-cell clones can be derived, which produce interferon-
(IFN-) and IL-17, many IL-17-producing clones appear to produce
neither IFN- nor IL-4. The significance of the observation that
IL-17 was produced by activated CD4+CD45RO memory T cells
has perhaps not been fully appreciated. One interpretation of this
observation is that there exists within the memory T-cell compartment a
population of T cells that were originally activated by unknown stimuli
to produce IL-17. Having acquired this differentiated, polarized state,
these cells are able to re-express IL-17 when subsequently restimulated
with relatively nonspecific stimuli such as phorbol 12-myristate
13-acetate (PMA) and ionomycin. This interpretation has been given
strong support by the recent observation that splenocytes from T-cell
receptor (TCR) transgenic mice could be driven to produce IL-17 when
primed with cognate peptide in the presence of microbial lipopeptides
[31
]. The study demonstrated that this outcome was not
observed when cells were stimulated with peptide and the known Th1
driver IL-12 [32
, 33
]. Characterization of
the cytokine expression profile of individual T cells within the
population by cytometric single-cell analysis revealed that the
IL-17-expressing cells represent a distinct population from the
traditional Th1 profile [34
35
36
] and are characterized
by the production of IL-17, GM-CSF, and tumor necrosis factor
(TNF-). This represents the first known physiological stimuli
capable of directing the development of IL-17-expressing T cells. These
data fit well with other observations that there is abundant IL-17 in
various conditions that are impacted by microbial pathogens, including
Helicobacter pylori-infected gastric mucosa
[37
] and synovial fluid of patients with Lyme arthritis
[31
].
Taken together, these data suggest a new paradigm for the consideration of IL-17 within the immune system. IL-17 may serve to mediate an adaptive immune response to pathogens that is characterized by a heavy reliance on cells thought to function primarily as mediators of the innate immune response. Thus, the immune system is able, by virtue of this memory T-cell response, to promote a more rapid recruitment of monocytes and neutrophils through IL-17-induced chemokine production [10 11 12 13 14 15 , 38 , 39 ]. Further, it is able to promptly begin to stimulate the production of additional myeloid cells through the production of GM-CSF by the activated IL-17/GM-CSF/TNF-producing T cells [31 ] and additional GM-CSF and G-CSF production from local IL-17-stimulated stromal cells [21 22 23 24 ]. However, the induction of ICAM by IL-17 acts to promote further T-cell responses, indicating the character of this adaptive response is not an exclusive reliance on phagocytic cells of the myeloid lineage.
The new IL-17s each appear to have very distinct expression patterns and therefore likely have distinct biological roles. The expression of IL-17 itself is very highly regulated, and IL-17 transcripts are essentially undetectable other than in select, activated T cells [11 ]. IL-17B is moderately expressed in several peripheral tissues as well as immune tissues [5 , 7 ]. IL-17C was found to be quite rare, but like IL-17, its expression is highly regulated in inflammatory conditions (unpublished results). The expression of the unpublished molecule, here termed IL-17D, appears to be particularly high in skeletal muscle and the nervous system, suggesting its biology is likely to be quite different from IL-17. The expression of IL-17E is strikingly low but can be detected by polymerase chain reaction (PCR) in various peripheral tissues [6 ]. IL-17F mRNA expression seems most similar to IL-17, with expression generally very low, but clearly detectable in activated populations of T cells [8 , 9 ]. Of these new members of the IL-17 family, IL-17E and IL-17F are currently the best characterized and so will be described in greater detail.
IL-17E has potent inflammatory effects in vitro and in vivo. Initial
characterization of IL-17E indicated that it, analogous to IL-17, was
able to stimulate activation of nuclear factor 
B (NF-B), a
transcription factor that contributes to the signal transduction of
several important proinflammatory molecules including TNF, IL-1ß, and
Toll-related receptors [40
41
42
]. Consistent with this,
it was shown to induce production of IL-8, a downstream target of each
of these signaling pathways. Recently, the action of IL-17E has been
characterized in the transgenic mouse setting [43
].
Overexpression of IL-17E resulted in profound alterations of the immune
system. Several features of the response had Th 2-like character
[44
, 45
]. The mice displayed eosinophilia
and increased serum immunoglobulin (Ig)E and IgG1 but not IgG2a. Serum
levels of IL-13 and IL-5 were elevated. Further, elevated gene
expression of several Th2 cytokines, including IL-4, IL-5, IL-10, and
IL-13, was observed in multiple tissues. However, although the systemic
response had Th2-like aspects, there were markedly different
tissue-specific expression patterns of cytokines, chemokines, and
adhesion molecules. For instance, high levels of TNF and ICAM were
expressed in liver. Elevated levels of G-CSF were expressed in several
tissues and likely contributed to the substantial neutrophilia
displayed in these mice. Moreover, exposure to IL-17E induced
pathological changes in multiple tissues, particularly liver, heart,
and lung, characterized by mixed inflammatory cell infiltration,
epithelial hyperplasia, and hypertrophy. Thus, IL-17E appears to be a
unique pleiotrophic cytokine that engages a systemic Th 2-like response
with tissue-specific immunological and pathological changes.
The gene encoding human IL-17F is located adjacent to IL-17 (human genomic sequence in clone RP11-935B23; Genbank accession AL355513) [8 ]. IL-17 and IL-17F share 44% amino acid identity, whereas the other members of the IL-17 family share a more limited 15–27% amino acid identity, suggesting that IL-17A and IL-17F form a distinct subgroup within the IL-17 family. As mentioned above, IL-17F is produced by activated T cells. Whether this expression is in precisely the same population of cells that express IL-17 and whether there are differences in the stimuli that induce their expression are unresolved questions. IL-17F has also been demonstrated in activated monocytes [9 ]. IL-17F appears to have similar biological actions as IL-17 [8 ] and is able to promote the production of IL-6, IL-8, and G-CSF from a wide variety of cells. Similar to IL-17, it is able to induce cartilage matrix release and inhibit new cartilage matrix synthesis. Thus, like IL-17, IL-17F may potentially contribute to the pathology of inflammatory disorders such as rheumatoid arthritis (RA) [46 47 48 49 50 ]. IL-17F has also been shown to induce transforming growth factor-ß (TGF-ß) expression in human umbilical vein endothelial cells and decrease their ability to undergo capillary tube formation, suggesting a potential ability to inhibit angiogenesis [9 ].
|
TOPABSTRACTDISCOVERY OF THE INTERLEUKIN-17...BIOLOGICAL ACTIONS OF IL-17...STRUCTURE OF THE IL-17sIL-17RIL-17 SIGNALINGIL-17 IN DISEASECONCLUSIONREFERENCES |
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B
and mitogen-activated protein kinase (MAPK) signaling pathways
[2
, 5
, 6
, 51
,
52
] and thus use signaling systems that are broadly
distributed across metazoan evolution [53
]. To better
understand the character of the IL-17s, the crystal structure of one of
the family members, IL-17F, has been determined recently
[8
]. Unexpectedly, the structure of IL-17F reveals that
the protein adopts a cysteine knot fold and suggests that the family
may have a relationship to the cysteine knot superfamily of proteins
[54
, 55
]. IL-17F folds in a manner quite
similar to that of nerve growth factor (NGF) [56
] and
the other neurotrophins [57
]. In addition, IL-17F and
NGF exist as dimers. The IL-17 family does not have any appreciable
sequence identity with the neurotrophins. The cysteine knot superfamily
is a diverse family and includes other proteins, such as the endocrine
glycoprotein hormones (e.g., chorionic gonadotropin), the
platelet-derived growth factors (PDGFs), and the TGF-ß family, which
also display limited sequence similarity [54
]. Although
IL-17 folds in a manner highly analogous to the cysteine knot
superfamily, one of the cononical cysteine pairs, the pair that links
through the ring formed by the other two pairs and thereby forms the
"knot," is not present. Instead, a third cysteine bridge is formed
by a spatially distinct pair of cysteines. Thus, although the members
of IL-17 family clearly adopt a cysteine knot fold, actual evolutionary
membership within the family cannot be assumed. The tertiary structural similarity between the IL-17s and the neurotrophins raises some interesting speculations. The neurotrophins bind to two classes of receptors [58 59 60 61 ], the Trk tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Neither the Ig domains within the extracellular domains of the Trk receptors nor the cysteine-rich extracellular domains that characterize membership in the TNF receptor family bear obvious similarity to the IL-17R. However, TNF has clear similarities to IL-17 in its ability to modulate immune function and promote an inflammatory response [40 ]. Another interesting speculation relates to the Drosophila protein späztle [62 , 63 ], which has been predicted to adopt a neurotrophin fold [64 ] and has been shown genetically to be an endogenous ligand for the Drosophila Toll receptor [65 , 66 ]. The Toll receptors are members of the leucine-rich repeat superfamily of proteins [67 68 69 70 ] and are clearly not related to the IL-17Rs. Nonetheless, it is possible that the IL-17 system may in some manner relate to this ancient, innate immune system.
|
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B and similar downstream
effector molecules. IL-17Rh1 was first shown as EVI27, a protein
encoded whose expression was up-regulated as a result of retroviral
integration in BXH2 murine myeloid leukemias [73
].
IL-17F, which has similar activity to IL-17, also appears able to
interact with the IL-17R (unpublished results), although the low
affinity of this interaction makes it clear that additional components
remain to be identified. |
TOPABSTRACTDISCOVERY OF THE INTERLEUKIN-17...BIOLOGICAL ACTIONS OF IL-17...STRUCTURE OF THE IL-17sIL-17RIL-17 SIGNALINGIL-17 IN DISEASECONCLUSIONREFERENCES |
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to the inflamed tissue
[51
]. The matrix degradation results from up-regulation
of inducible nitric oxide synthase (iNOS) and NO in chondrocytes
through a tyrosine kinase-dependent cascade, which is protein kinase A
(PKA)- and, to a lesser extent, protein kinase C (PKC)-dependent
[75
, 78
]. IL-17 activates all three
subgroups of MAPKs, which are the p44 and p42 extracellular
signal-regulated kinases (ERK1 and ERK2), stress-induced Jun
NH2-terminal kinases (JNK), and p38 [52
,
75
, 79
, 80
]. The IL-17-induced
activation of JNKs (JNK1 and JNK2) results in up-regulation of iNOS and
cyclooxygenase-2 (COX-2) genes [75
]. NF-B activation
by IL-17 was seen in human fibroblasts [4
,
28
], intestinal epithelial cells [52
], and
chondrocyte cultures [75
, 78
]. The
mechanisms by which IL-17 activates NF-B are not resolved but appear
to be dependent on TNF receptor-associated factor (TRAF)-6
[52
, 81
]. IL-17 has also been postulated to be a major vehicle by which T cells can communicate with the hematopoietic system [82 ]. For example, fibroblasts cultured with IL-17 were shown to support the growth of human CD34+ hematopoietic progenitor cells and direct their maturation toward neutrophils [4 ]. More recently, it was shown that adenovirus-mediated gene transfer of murine IL-17 cDNA targeted to the liver stimulates granulopoiesis in mice [83 ]. In the hematopoietic system, using human monocytic leukemia cell line U937, IL-17 was shown to trigger tyrosine phosphorylation of several members of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways [84 ]. These included Tyk2, JAK1, -2, and –3, and STAT 1, 2, 3, and 4, suggesting the possibility that the JAK/STAT pathway may be involved in mediating biological effects of IL-17.
Recently, we have shown that another member of IL-17 family, IL-17E,
also activates NF-B [6
]. Furthermore, IL-17E and
recently characterized IL-17F [8
] promote the production
IL-8 and IL-6 in vitro from responsive cell lines, activities shared
with IL-17 and suggesting that the members of this family are capable
of engaging similar intracellular machinery.
|
TOPABSTRACTDISCOVERY OF THE INTERLEUKIN-17...BIOLOGICAL ACTIONS OF IL-17...STRUCTURE OF THE IL-17sIL-17RIL-17 SIGNALINGIL-17 IN DISEASECONCLUSIONREFERENCES |
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IL-17 and airway neutrophils
IL-17 can also play a proinflammatory role in the airways by
recruiting and activating neutrophils [18
19
20
,
104
, 105
]. Exacerbations of obstructive
airway diseases, including bronchial asthma and chronic obstructive
pulmonary disease (COPD), have resulted in increased neutrophilic
granulocytes that are not associated with any detectable infection
[106
]. The neutrophil recruitment by IL-17 is mediated
in part by CXC chemokine release [20
] or by induction of
endogenous tachykinins that act on natural killer (NK)-1 receptors to
mediate neutrophil recruitment [18
]. In addition to
neutrophil recruitment, IL-17 can also stimulate neutrophil activity in
the airways, because it stimulates release of neutrophil-activating
cytokines IL-6 and IL-8 from bronchial epithelium and fibroblasts
[4
]. The IL-17-induced release of IL-6 and IL-8 is
potentiated by IL-1ß in bronchial epithelial cells [51
,
107
], which in turn can be regulated by IL-17, because
increased IL-1ß is present in obstructive airway diseases
[108
].
IL-17 in other diseases of chronic inflammation
Overproduction of IL-17 has been associated with several chronic
disease conditions, suggesting a role in these diseases. Several
studies point to the association among IL-17, transplant rejection
[14
, 109
110
111
], systemic sclerosis
[112
], psoriasis [27
, 28
,
113
], and promotion of tumor growth
[114
115
116
].
Blocking the effects of IL-17 using IL-17R:Fc inhibits proliferative responses of T cells to allo-antigens and also significantly prolongs major histocompatibility complex (MHC)-mismatched, nonvascularized and vascularized cardiac allograft survival in animal models [109 , 110 ]. Systemic multiple sclerosis (SSc) is a connective tissue disease of unknown etiology characterized by fibrosis of the skin, lung, and gastrointestinal tract and by microvascular abnormalities of the skin and visceral organs [117 ]. Increased IL-17 expression is seen in CD4+ T cells in the lymphocytes from peripheral blood and fibrotic lesions of the skin and the lung of affected patients [112 ]. Similarly, a presence of IL-17 is seen in CD4+ and CD8+ T-cell clones derived from biopsies from lesional psoriatic skin but not in nonlesional control biopsies [27 , 113 ]. Last but not least, expression of IL-17 is seen in >50% of ovarian [114 ], endometrial [114 ], and cervical cancers [115 ]. Furthermore, in selected cervical cancer cell lines, IL-17 exhibited angiogenic effects, as tumors from IL-17-transducted cell lines resulted in increased tumor size [115 ], possibly because of IL-17-mediated, increased expression of IL-6 and macrophage recruitment.
|
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Received September 28, 2001; accepted October 1, 2001.
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TOPABSTRACTDISCOVERY OF THE INTERLEUKIN-17...BIOLOGICAL ACTIONS OF IL-17...STRUCTURE OF THE IL-17sIL-17RIL-17 SIGNALINGIL-17 IN DISEASECONCLUSIONREFERENCES |
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E. Lubberts, P. Schwarzenberger, W. Huang, J. R. Schurr, J. J. Peschon, W. B. van den Berg, and J. K. Kolls Requirement of IL-17 Receptor Signaling in Radiation-Resistant Cells in the Joint for Full Progression of Destructive Synovitis J. Immunol., September 1, 2005; 175(5): 3360 - 3368. [Abstract] [Full Text] [PDF]
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S. A. Khader, J. E. Pearl, K. Sakamoto, L. Gilmartin, G. K. Bell, D. M. Jelley-Gibbs, N. Ghilardi, F. deSauvage, and A. M. Cooper IL-23 Compensates for the Absence of IL-12p70 and Is Essential for the IL-17 Response during Tuberculosis but Is Dispensable for Protection and Antigen-Specific IFN-{gamma} Responses if IL-12p70 Is Available J. Immunol., July 15, 2005; 175(2): 788 - 795. [Abstract] [Full Text] [PDF]
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F. McAllister, A. Henry, J. L. Kreindler, P. J. Dubin, L. Ulrich, C. Steele, J. D. Finder, J. M. Pilewski, B. M. Carreno, S. J. Goldman, et al. Role of IL-17A, IL-17F, and the IL-17 Receptor in Regulating Growth-Related Oncogene-{alpha} and Granulocyte Colony-Stimulating Factor in Bronchial Epithelium: Implications for Airway Inflammation in Cystic Fibrosis J. Immunol., July 1, 2005; 175(1): 404 - 412. [Abstract] [Full Text] [PDF]
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 F. Shen, M. J. Ruddy, P. Plamondon, and S. L. Gaffen Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-{alpha}-induced genes in bone cells J. Leukoc. Biol., March 1, 2005; 77(3): 388 - 399. [Abstract] [Full Text] [PDF]
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 C. L. Langrish, Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein, and D. J. Cua IL-23 drives a pathogenic T cell population that induces autoimmune inflammation J. Exp. Med., January 18, 2005; 201(2): 233 - 240. [Abstract] [Full Text] [PDF]
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S. Yamazaki, T. Muta, S. Matsuo, and K. Takeshige Stimulus-specific Induction of a Novel Nuclear Factor-{kappa}B Regulator, I{kappa}B-{zeta}, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization J. Biol. Chem., January 14, 2005; 280(2): 1678 - 1687. [Abstract] [Full Text] [PDF]
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 A. Linden, M. Laan, and G. P. Anderson Neutrophils, interleukin-17A and lung disease Eur. Respir. J., January 1, 2005; 25(1): 159 - 172. [Abstract] [Full Text] [PDF]
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 N. Oda, P. B. Canelos, D. M. Essayan, B. A. Plunkett, A. C. Myers, and S.-K. Huang Interleukin-17F Induces Pulmonary Neutrophilia and Amplifies Antigen-induced Allergic Response Am. J. Respir. Crit. Care Med., January 1, 2005; 171(1): 12 - 18. [Abstract] [Full Text] [PDF]
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X. K. Liu, X. Lin, and S. L. Gaffen Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17 J. Biol. Chem., December 10, 2004; 279(50): 52762 - 52771. [Abstract] [Full Text] [PDF]
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D. T. Nardelli, M. A. Burchill, D. M. England, J. Torrealba, S. M. Callister, and R. F. Schell Association of CD4+ CD25+ T Cells with Prevention of Severe Destructive Arthritis in Borrelia burgdorferi-Vaccinated and Challenged Gamma Interferon-Deficient Mice Treated with Anti-Interleukin-17 Antibody Clin. Vaccine Immunol., November 1, 2004; 11(6): 1075 - 1084. [Abstract] [Full Text] [PDF]
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C.-Y. Kao, Y. Chen, P. Thai, S. Wachi, F. Huang, C. Kim, R. W. Harper, and R. Wu IL-17 Markedly Up-Regulates {beta}-Defensin-2 Expression in Human Airway Epithelium via JAK and NF-{kappa}B Signaling Pathways J. Immunol., September 1, 2004; 173(5): 3482 - 3491. [Abstract] [Full Text] [PDF]
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 M. D. Dodon, Z. Li, S. Hamaia, and L. Gazzolo Tax protein of human T-cell leukaemia virus type 1 induces interleukin 17 gene expression in T cells J. Gen. Virol., July 1, 2004; 85(7): 1921 - 1932. [Abstract] [Full Text] [PDF]
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M. J. Ruddy, F. Shen, J. B. Smith, A. Sharma, and S. L. Gaffen Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment J. Leukoc. Biol., July 1, 2004; 76(1): 135 - 144. [Abstract] [Full Text] [PDF]
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M. J. Ruddy, G. C. Wong, X. K. Liu, H. Yamamoto, S. Kasayama, K. L. Kirkwood, and S. L. Gaffen Functional Cooperation between Interleukin-17 and Tumor Necrosis Factor-{alpha} Is Mediated by CCAAT/Enhancer-binding Protein Family Members J. Biol. Chem., January 23, 2004; 279(4): 2559 - 2567. [Abstract] [Full Text] [PDF]
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S. Nakae, A. Nambu, K. Sudo, and Y. Iwakura Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice J. Immunol., December 1, 2003; 171(11): 6173 - 6177. [Abstract] [Full Text] [PDF]
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R.-B. Yang, C. K. D. Ng, S. M. Wasserman, L. G. Komuves, M. E. Gerritsen, and J. N. Topper A Novel Interleukin-17 Receptor-like Protein Identified in Human Umbilical Vein Endothelial Cells Antagonizes Basic Fibroblast Growth Factor-induced Signaling J. Biol. Chem., August 29, 2003; 278(35): 33232 - 33238. [Abstract] [Full Text] [PDF]
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W. H. Faour, A. Mancini, Q. W. He, and J. A. Di Battista T-cell-derived Interleukin-17 Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of the p38 Mitogen-activated Protein Kinase Cascade: ROLE OF DISTAL SEQUENCES IN THE 3'-UNTRANSLATED REGION OF COX-2 mRNA J. Biol. Chem., July 11, 2003; 278(29): 26897 - 26907. [Abstract] [Full Text] [PDF]
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K. I. Happel, M. Zheng, E. Young, L. J. Quinton, E. Lockhart, A. J. Ramsay, J. E. Shellito, J. R. Schurr, G. J. Bagby, S. Nelson, et al. Cutting Edge: Roles of Toll-Like Receptor 4 and IL-23 in IL-17 Expression in Response to Klebsiella pneumoniae Infection J. Immunol., May 1, 2003; 170(9): 4432 - 4436. [Abstract] [Full Text] [PDF]
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K. Ikeda, H. Nakajima, K. Suzuki, S.-i. Kagami, K. Hirose, A. Suto, Y. Saito, and I. Iwamoto Mast cells produce interleukin-25 upon Fcepsilon RI-mediated activation Blood, May 1, 2003; 101(9): 3594 - 3596. [Abstract] [Full Text] [PDF]
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 M. D. Silverman, D. O. Zamora, Y. Pan, P. V. Texeira, S.-H. Baek, S. R. Planck, and J. T. Rosenbaum Constitutive and Inflammatory Mediator-Regulated Fractalkine Expression in Human Ocular Tissues and Cultured Cells Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1608 - 1615. [Abstract] [Full Text] [PDF]
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G.-X. Zhang, B. Gran, S. Yu, J. Li, I. Siglienti, X. Chen, M. Kamoun, and A. Rostami Induction of Experimental Autoimmune Encephalomyelitis in IL-12 Receptor-{beta}2-Deficient Mice: IL-12 Responsiveness Is Not Required in the Pathogenesis of Inflammatory Demyelination in the Central Nervous System J. Immunol., February 15, 2003; 170(4): 2153 - 2160. [Abstract] [Full Text] [PDF]
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S. Aggarwal, N. Ghilardi, M.-H. Xie, F. J. de Sauvage, and A. L. Gurney Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17 J. Biol. Chem., January 10, 2003; 278(3): 1910 - 1914. [Abstract] [Full Text] [PDF]
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 J. K. Kolls, S. T. Kanaly, and A. J. Ramsay Interleukin-17: An Emerging Role in Lung Inflammation Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 9 - 11. [Full Text] [PDF]
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T. Starnes, H. E. Broxmeyer, M. J. Robertson, and R. Hromas Cutting Edge: IL-17D, a Novel Member of the IL-17 Family, Stimulates Cytokine Production and Inhibits Hemopoiesis J. Immunol., July 15, 2002; 169(2): 642 - 646. [Abstract] [Full Text] [PDF]
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