HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takeda, A. Articles by Yoshida, H. Search for Related Content PubMed PubMed Citation Articles by Takeda, A. Articles by Yoshida, H.

Cutting Edge: Role of IL-27/WSX-1 Signaling for Induction of T-Bet Through Activation of STAT1 During Initial Th1 Commitment¹

Atsunobu Takeda^*,, Shinjiro Hamano, Atsushi Yamanaka^*,, Toshikatsu Hanada^*, Tatsuro Ishibashi, Tak W. Mak^¶, Akihiko Yoshimura^* and Hiroki Yoshida^2,*,

^* Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, and Departments of Ophthalmology and Parasitology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; PRESTO, Japan Science and Technology Corporation, Kawaguchi, Saitama, Japan; and ^¶ Ontario Cancer Institute and Departments of MedicalBiophysics and Immunology, University of Toronto, Toronto, Ontario, Canada

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
WSX-1 is a member of the class I cytokine receptor family with homology to IL-12R2 and is essential for the initial mounting of Th1 responses. STAT1 interacts with tyrosine-phosphorylated WSX-1, and the conserved tyrosine residue of the cytoplasmic domain of WSX-1 is essential for transcriptional activation of STAT1. IL-27 stimulation induced STAT1 phosphorylation in wild-type but not in WSX-1-deficient naive CD4⁺ T cells. Although IL-27 did not directly induce IFN- production by wild-type CD4⁺ T cells, IL-12-dependent IFN- production was augmented by IL-27 stimulation in wild-type naive CD4⁺ T cells but was impaired in WSX-1-deficient naive CD4⁺ T cells. Additionally, IL-27 stimulation induced T-bet and IL-12R2 expression in wild-type, but not in WSX-1-deficient, CD4⁺ T cells. Thus, during the initiation of Th1 differentiation, the IL-27/WSX-1 signaling system plays a pivotal role by STAT1-mediated T-bet induction before the IL-12R system.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The regulation of the differentiation of naive CD4⁺ T cells into either Th1 or Th2 cells is a critical process when naive CD4⁺ T cells encounter Ag. Th1 and Th2 cells develop from the same Th precursor cells, and cytokines play roles for the regulation of differentiation. IL-12 promotes IFN- production and the differentiation of naive CD4⁺ T cells into Th1 cells via STAT4 (1). IL-12R2 chain expression is rapidly up-regulated by signals, including TCR stimulation, and is required for STAT4 activation. T-bet, a key transcriptional factor for Th1 initiation, is exclusively expressed in Th1 cells and is a potent transactivator of the IFN- gene (2). Although the role of T-bet for Th1 induction is clear, the induction mechanism for T-bet has been controversial (2, 3, 4, 5).

WSX-1 is a novel class I cytokine receptor with homology to the IL-12Rs and is highly expressed in lymphoid tissues (6, 7). WSX-1 encodes a putative cytokine receptor with a WSX signature motif in its extracellular domain and a box 1 motif in its intracellular domain. There is one conserved tyrosine residue between human and murine WSX-1, suggesting that WSX-1 is capable of signal transduction by tyrosine phosphorylation. Analyses of WSX-1-deficient mice revealed that WSX-1 is required for normal production of IFN- by naive CD4⁺ T cells, indicating that WSX-1 signaling is essential for the initial mounting of Th1 (8).

Reportedly, IL-27 is a candidate ligand for WSX-1 (9). However, the downstream signaling pathway of IL-27/WSX-1 system has not been elucidated. In the present study, we demonstrated that STAT1 is activated through interaction with the tyrosine residue in the cytoplasmic domain of WSX-1. In addition, we found that IL-27-dependent tyrosine phosphorylation of STAT1 and IL-12-dependent IFN- production were abrogated in WSX-1-deficient naive CD4⁺ T cells. Furthermore, IL-27 induced expression of T-bet through WSX-1 signaling in wild-type naive CD4⁺ T cells. In toto, these results showed that IL-27/WSX-1 signaling is important for the initial commitment of Th1 responses.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Cells

HEK293 cells were cultured in DMEM containing 10% calf serum. Ba/F3 was maintained in RPMI 1640 medium containing 10% FCS and 1 ng/ml murine IL-3. Stable WSX-1-expressing Ba/F3 transformants were obtained by transfection of the Ba/F3 cells with pCMV14 (Sigma-Aldrich, St. Louis, MO) carrying 3xFlag-tagged full-length WSX-1 cDNA. Stable Ba/F3 transformants expressing both WSX-1 and STAT4 were obtained similarly.

Reagents

Murine rIL-12 and anti-IFN- neutralizing Ab were purchased from R&D Systems (Minneapolis, MN). Anti-STAT1 and anti-phosphotyrosine (PY)³-STAT1 Abs were purchased from New England Biolabs (Beverly, MA); anti-STAT3, -4, and -5b Abs were from Santa Cruz Biotechnology (Santa Cruz, CA); anti-mouse IgG-HRP and anti-rabbit IgG-HRP Abs were from Jackson ImmunoResearch (West Grove, PA); and anti-FLAG M2 was from Sigma-Aldrich. Anti-T-bet Abs were kindly provided by Dr. L. Glimcher (Harvard School of Public Health, Boston, MA).

Constructs

For expression of the IL-12R2/WSX-1 chimeric receptor (2/W), a cDNA encoding the extracellular domain and a portion of the cytoplasmic domain containing the box 1 region of IL-12R2 was fused to cDNA fragments encoding the cytoplasmic domain of WSX-1 containing the conserved tyrosine residue. The chimeric cDNA was subcloned into pCMV14–3xFLAG. One substitution mutant of 2/W, 2/W-mt (mutation at the conserved tyrosine residue of mouse WSX-1 into phenylalanine), was derived from 2/W.

Immunoprecipitation and Western blot analysis

For immunoprecipitation, cells were lysed in a lysis buffer containing protease inhibitors and vanadate and immunoprecipitated with the indicated Abs. Precipitated immunocomplexes or total cell lysates were resolved by SDS-PAGE and immunoblotted with indicated Abs.

In vitro GST pull-down assay

GST fusion protein containing the cytoplasmic domain of WSX-1 was expressed in Escherichia coli strains BL21 or TKB1, and purified with glutathione-Sepharose beads. Cell lysates from splenocytes of wild-type mice were added to the fusion proteins bound to Sepharose beads. Bound proteins were examined by electrophoresis and immunoblotting with indicated Abs.

Luciferase assay

IL-12-dependent STAT1 reporter activity was assayed as described previously (10). HEK293 cells were plated at 2 x 10⁵/well on 6-well dishes. Cells were transfected with indicated combination of the genes by the calcium phosphate method. After stimulation with IL-12, luciferase activity was measured using the Promega luciferase assay system (Promega, Madison, WI) according to the manufacturer’s directions. Luciferase activity was normalized to -galactosidase activity.

IL-27-dependent STAT1 phosphorylation

CD4⁺ T cells were purified from wild-type, WSX-1-deficient, or IFN--deficient mice by MACS. Cells were activated with plate-bound anti-CD3 Ab (145-2C11; 10 µg/ml; BD PharMingen, San Diego, CA) for 24 h, washed, and stimulated with IL-27 in the presence of anti-IFN- neutralizing Abs (1 µg/ml). Cell lysates were prepared, electrophoresed, blotted, and then visualized with anti-PY-STAT1 Ab.

Semiquantitative RT-PCR analysis of IL-12R2 expression

Sorted naive CD4⁺ T cells were stimulated with plate-bound anti-CD3 mAb (1 µg/ml) plus anti-CD28 mAb (1 µg/ml) and anti-IFN- neutralizing Ab in the absence or presence of IL-27. RNA was prepared with TRIzol (Life Technologies, Rockville, MD). For semiquantitative RT-PCR, cDNA was reverse transcribed from total RNA with oligo(dT)₁₆ primers and murine leukemia virus reverse transcriptase (PerkinElmer, Wellesley, MA). First, the amounts of cDNA were adjusted by quantitating the amount of G3PDH PCR product using the ABI Prism 7000 sequence detection system (ABI, Foster City, CA). Then, the same amounts of cDNA normalized to the G3PDH were amplified for IL-12R2. The following primers were used: IL-12R2, sense, 5'-ACT GTC AGA GAG CCA AGG AG-3', and antisense, 5'-GTG CCC ACC GTG ATG ATA G-3'.

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Janus kinase (JAK)1 and STAT1 associate with WSX-1

Cytokine receptors constitutively interact with JAK that phosphorylates the receptors on tyrosine residues in the intracellular domain (11). To investigate whether WSX-1 interacts with JAK, murine WSX-1-expressing Ba/F3 lines (Ba/F3-WSX-1) were established. We found that JAK1, but not other JAKs, was coprecipitated with WSX-1 (Fig. 1A). Similarly, WSX-1 is precipitated with anti-JAK1 Ab, but not with control anti-Myc Ab in WSX-1-expressing cells. Cytoplasmic domains of cytokine receptors, when phosphorylated by JAKs, bind STATs (11). Among tyrosine residues present in the cytoplasmic domain of mouse WSX-1, only Y609 is conserved between human and murine (6, 7). To investigate whether STATs bind to Y609 of WSX-1, an in vitro pull-down assay was conducted. WSX-1 protein was expressed as a GST fusion protein in E. coli strains BL21 or the tyrosine kinase-positive derivative TKB1. GST-fused cytoplasmic domain of WSX-1, which was phosphorylated when expressed in TKB1 (data not shown), was able to associate with STAT1 but not other STATs examined, including STAT3, -4, and -5b (Fig. 1B). Unphosphorylated form of GST-WSX-1 produced in BL21 did not associate with any STATs. Association of WSX-1 with STAT1 was further confirmed using WSX-1-expressing Ba/F3 cell lines, Ba/F3-WSX-1. As shown in Fig. 1C, in cell lysates of Ba/F3-WSX-1 treated with pervanadate for increase of tyrosine phosphorylation, only STAT1 was revealed to interact with WSX-1. No association of STAT4 with WSX-1 was detected in Ba/F3-WSX-1 overexpressing STAT4 (Fig. 1C). These results indicate that only STAT1, but not other STATs including STAT4, can be recruited to WSX-1 in a phosphorylation-dependent fashion.

View larger version (26K): [in this window] [in a new window]   FIGURE 1. Association of STAT1 with tyrosine-phosphorylated WSX-1. A, Lysates of Ba/F3-WSX-1 cell lines were incubated with anti-FLAG M2 Ab for precipitation of FLAG-tagged WSX-1 or with a control Ab. Precipitates or total cell lysates (TCL) were electrophoresed, blotted, and probed with indicated anti-JAK Abs. Reciprocal immunoprecipitation was conducted by treating cell lysates with anti-JAK1 Ab. Precipitates or total cell lysates were analyzed with anti-FLAG M2 Ab. B, Splenocyte lysates were incubated with GST-WSX-1 produced in either BL21 or TKB1 immobilized on glutathione-Sepharose beads. Bound proteins were electrophoresed, blotted, and visualized with anti-STAT1, -3, -4, or -5b Abs. The integrity and quality of the GST-fused WSX-1 protein were confirmed with anti-GST Ab (bottom panel). C, Ba/F3-WSX-1 cells were either untreated (-) or treated (+) with pervanadate. Immunoprecipitations were performed with anti-FLAG M2 Ab, and precipitates were examined for the coprecipitation of STAT1, -3, or -5b with indicated Ab. Ba/F3-WSX-1-STAT4 cells were treated likewise for the association of STAT4 with WSX-1 (bottom panel). Total cell lysates were examined for verification of the same expression level of each STAT after vanadate treatment. All experiments were repeated three times with similar results.

Recently, IL-27, an IL-12-related cytokine, has been reported as a candidate ligand for WSX-1 (9). However, neither Ba/F3-WSX-1 cells nor Ba/F3-WSX-1/STAT4 cells responded to IL-27 by either proliferation or protein tyrosine phosphorylation (data not shown), due presumably to lack of component(s) of the WSX-1 receptor complex and/or downstream signaling pathways in Ba/F3 cells. For circumvention, we constructed a chimeric receptor (2/W) where the extracellular domain and box 1 is of IL-12R2 and the cytoplasmic domain is of WSX-1. When coexpressed with IL-12R1, exogenous IL-12 can ligate IL-12R1 and 2/W and may reconstitute WSX-1 signaling, at least partly. Thus, ligand-induced transcriptional activation of the reporter gene by STAT1 was tested by cotransfecting the IL-12R1, the 2/W chimeric receptor, and the IFN- activation site (GAS) luciferase reporter gene into cells. As shown in Fig. 2A, IL-12 treatment increased the STAT1 transcriptional activity by 4.4-fold in cells transfected with IL-12R1 and the 2/W chimeric receptor (1 plus 2/W) while the same treatment increased GAS-luciferase activity by only 1.6-fold in IL-12R1- plus -2-expressing cells (1 plus 2). We also constructed a substitution mutant form of 2/W Y824F (mutation at the conserved tyrosine residue of WSX-1 into phenylalanine). Then, we determined the transcriptional activation by STAT1 under the 2/W mutant receptor. GAS-luciferase activity in cells expressing 1 plus 2/W mutant Y824F (1 plus 2/W-mt) was not augmented by IL-12 treatment over that observed in 1- plus 2-expressing cells (Fig. 2A). STAT1 is reported to dock to the sequence pYDKPH in the IFNR (12, 13). The pYEKHF motif at the conserved tyrosine residue in WSX-1 shares amino acid similarities to the STAT1 docking site of the IFNR, pYDKPH. Thus, it is conceivable that STAT1 is activated by interaction with the WSX-1 at the conserved tyrosine residue upon ligand binding.

View larger version (24K): [in this window] [in a new window]   FIGURE 2. STAT1 activation by WSX-1 signaling. A, HEK293 cells were transfected with a plasmid mixture containing the GAS luciferase reporter gene, IL-12R1-expressing constructs (1), and either wild-type (2/W) or Y824F mutant (2/W-mt) chimeric receptor, along with -galactosidase gene or untreated (mock). After 24 h, indicated transfected cells were incubated with () or without () IL-12 (100 ng/ml for maximum induction of GAS-luciferase activity) for 12 h, and cell extracts were prepared for luciferase activity. *, p < 0.01 by paired t test. Data normalized with the -galactosidase activity from triplicate experiments are shown. Experiments were repeated three times with similar results. B, CD4+ T cells from spleens of either WSX-1+/- or WSX-1-/- mice were activated with plate-bound anti-CD3 Ab (10 µg/ml) for 24 h. The activated cells were washed twice, and then incubated in the presence of IL-27 with anti-IFN- neutralizing Ab (1 µg/ml) for the indicated periods. Phosphorylation of STAT1 in whole cell lysate was analyzed with anti-PY-STAT1 Ab. IFN--/- CD4+ T cells were treated similarly, and STAT1 phosphorylation was observed. Filters were stripped and reprobed with anti-STAT1 Ab as internal controls.

IFN-

WSX-1 signaling provides for IL-12-induced IFN- production

Because both IL-27 and WSX-1 have been implicated in Th1 responses (6, 8, 9), we next examined whether IL-27 induced IFN- production in naive CD4⁺ T cells. Purified naive CD4⁺ T cells from either WSX-1^+/- or WSX-1^-/- mice were cultured for 3 days in the presence of APC and Con A with or without IL-27, and the culture supernatants were collected for IFN- production (Fig. 3). Whereas IL-12 plus IL-27 stimulation induced IFN- production by WSX-1^+/- naive CD4⁺ T cells, the same stimulation did not lead to IFN- production by WSX-1^-/- CD4⁺ T cells. IFN- production was induced in neither WSX-1^+/- nor WSX-1^-/- CD4⁺ T cells stimulated solely with IL-27. Taken together, we consider that IL-27/WSX-1 signaling does not directly induce IFN- production, but it provides for responsiveness of naive CD4⁺ T cells to IL-12 and the consequent IFN- production.

View larger version (25K): [in this window] [in a new window]   FIGURE 3. IL-27 provides for IL-12-mediated IFN- production. Sorted CD4+CD45RBhigh naive T cells from WSX-1+/- (left) or WSX-1-/- (right) mice were stimulated with Con A, IL-27, and increasing doses of IL-12 in the presence of irradiated spleen cells for 72 h. Culture supernatants were collected and IFN- production determined in triplicate. One representative result of three experiments with similar results is shown.

Lines of evidence demonstrate that T-bet is a Th1-specific transcription factor and is critical for Th1 responses (2). Recent studies revealed that T-bet is up-regulated through STAT1 activation (4, 5). In addition, it is also reported that expression of T-bet induces IL-12R2 expression (5). Because WSX-1 signaling involves STAT1 activation and is critical for IL-12-dependent IFN- production, we determined whether IL-27 induced T-bet and subsequent IL-12R2 expression in a WSX-1-dependent manner. Purified naive CD4⁺ T cells from either WSX-1^+/- or WSX-1^-/- mice were cultured with anti-CD3 Ab with or without IL-27 in the presence of anti-IFN- neutralizing Ab. As expected, expression of T-bet was augmented by IL-27 treatment of the wild-type CD4⁺ T cells (Fig. 4A). However, the same treatment did not augment T-bet expression more than the basal level in WSX-1-deficient CD4⁺ T cells. RT-PCR analysis of the similarly treated cells revealed that IL-27 induced IL-12R2 expression in wild-type but not in WSX-1^-/- CD4⁺ T cells (Fig. 4B). These results indicate that IL-27/WSX-1 signaling is important for augmentation of T-bet expression and the following IL-12R2 expression by CD4⁺ naive T cells. Taken together, IL-27/WSX-1 signaling plays a pivotal role by STAT1-induced T-bet expression at the initial checkpoint of Th1 differentiation.

View larger version (52K): [in this window] [in a new window]   FIGURE 4. Induction of T-bet expression by IL-27 stimulation. A, CD4+ T cells from WSX-1+/- or WSX-1-/- mice were stimulated with plate-bound anti-CD3 Ab plus anti-CD28 Ab and anti-IFN- neutralizing Ab in the absence or presence of IL-27 for 48 h. Cell lysates were electrophoresed, blotted, and visualized with anti-T-bet Abs. The same filter was stripped and reprobed with anti-STAT5b Ab as internal controls. B, mRNAs were extracted from the cells similarly treated as in A. Same amounts of cDNA, adjusted to the amount of G3PDH measured by quantitative real-time PCR, were amplified for IL-12R2 expression. Experiments were repeated three times with similar results.

Despite the obvious role of T-bet for Th1 induction, its induction mechanism has been controversial. Szabo et al. (2) have suggested that the expression of T-bet is regulated by TCR signaling and STAT4-mediated IL-12R signaling. However, Mullen et al. (3) have reported that T-bet was induced and acted before STAT4 activation in Th1 development. In addition, this study suggested that T-bet expression was STAT4 independent. Furthermore, recent studies elucidated that T-bet was induced by an autocrine pathway involving IFN- and STAT1, independently of STAT4 (4, 5). In this study, we show that WSX-1 signaling augmented the expression of T-bet in stimulated naive CD4⁺ T cells (Fig. 4A). It is thus suggested that WSX-1 signaling plays an important role during the initial step of proper Th1 differentiation by expression of T-bet and the subsequent IL-12R2 expression. However, WSX-1 signaling is not the sine qua non of T-bet expression, because T-bet expression was detected in anti-CD3-stimulated naive T cells before IL-27 stimulation. Moreover, although not augmented by IL-27, we detected a higher level of T-bet expression in anti-CD3-stimulated WSX-1^-/- T cells than in wild-type T cells before IL-27 stimulation (Fig. 4A). WSX-1-deficient T cells may have higher sensitivity to antigenic stimulation as previously shown by the higher proliferation of WSX-1^-/- T cells in response to stimulation (8). Taken together, without WSX-1 signaling, the expression of T-bet and the following Th1 differentiation is initially impaired but may finally get to the normal level later.

In addition to the IL-12 and IL-12R pathway, newly identified cytokines and cytokine receptors have been revealed to play roles in Th1 responses (6, 8, 9, 14, 15). The IL-12/IL-12R system acts via STAT4 activation for IFN- production. IL-23 exerts its effects on activated/memory T cells for proliferation and IFN- production by STAT4 activation (14, 15). Discovery of IL-27 (9) and our current finding that IL-27/WSX-1 stimulation induces T-bet expression by naive CD4⁺ T cells through STAT1 activation identify the IL-27/WSX-1 signaling system as a key Th1 commitment step at which naive Th precursor cells commence differentiation into Th1 cells. Thus, various cytokines cooperate at different phases of T cell activation/differentiation to ensure optimal Th1 responses (for review, see Ref. 16). Further clarification of the paradigms of Th1 responses will provide approaches to therapeutic intervention against immunopathologies such as autoimmune diseases and infections.

	Acknowledgments

 
We thank Dr. L. Glimcher for anti-T-bet Abs, and A. Sasaki, T. Yoshida, K. Saeki, and members of the Project W for helpful discussion.

	Footnotes

 
¹ This study was supported in part by grants from the Ministry of Education, Science, Technology, Sports and Culture of Japan (to H.Y. and A.Y.).

² Address correspondence and reprint requests to Dr. Hiroki Yoshida, Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: hyoshida{at}bioreg.kyushu-u.ac.jp

³ Abbreviations used in this paper: PY, phosphotyrosine; 2/W, IL-12R2/WSX-1 chimeric receptor; 2/W-mt, 2/W mutant Y824F; JAK, Janus kinase; GAS, IFN- activation site.

Received for publication January 7, 2003. Accepted for publication March 19, 2003.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Murphy, K. M., W. Ouyang, J. D. Farrar, J. Yang, S. Ranganath, H. Asnagli, M. Afkarian, T. L. Murphy. 2000. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18:451.[Medline]
2. Szabo, S. J., S. T. Kim, G. L. Costa, X. Zhang, C. G. Fathman, L. H. Glimcher. 2000. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655.[Medline]
3. Mullen, A. C., F. A. High, A. S. Hutchins, H. W. Lee, A. V. Villarino, D. M. Livingston, A. L. Kung, N. Cereb, T. P. Yao, S. Y. Yang, S. L. Reiner. 2001. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907.[Abstract/Free Full Text]
4. Lighvani, A. A., D. M. Frucht, D. Jankovic, H. Yamane, J. Aliberti, B. D. Hissong, B. V. Nguyen, M. Gadina, A. Sher, W. E. Paul, J. J. O’Shea. 2001. T-bet is rapidly induced by interferon- in lymphoid and myeloid cells. Proc. Natl. Acad. Sci. USA 98:15137.[Abstract/Free Full Text]
5. Afkarian, M., J. R. Sedy, J. Yang, N. G. Jacobson, N. Cereb, S. Y. Yang, T. L. Murphy, K. M. Murphy. 2002. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4⁺ T cells. Nat. Immunol. 3:549.[Medline]
6. Chen, Q., N. Ghilardi, H. Wang, T. Baker, M. H. Xie, A. Gurney, I. S. Grewal, F. J. de Sauvage. 2000. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407:916.[Medline]
7. Sprecher, C. A., F. J. Grant, J. W. Baumgartner, S. R. Presnell, S. K. Schrader, T. Yamagiwa, T. E. Whitmore, P. J. O’Hara, D. F. Foster. 1998. Cloning and characterization of a novel class I cytokine receptor. Biochim. Biophys. Acta 246:82.
8. Yoshida, H., S. Hamano, G. Senaldi, T. Covey, R. Faggioni, S. Mu, M. Xia, A. C. Wakeham, H. Nishina, J. Potter, et al 2001. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity 15:569.[Medline]
9. Pflanz, S., J. C. Timans, J. Cheung, R. Rosales, H. Kanzler, J. Gilbert, L. Hibbert, T. Churakova, M. Travis, E. Vaisberg, et al 2002. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4⁺ T cells. Immunity 16:779.[Medline]
10. Saito, H., Y. Morita, M. Fujimoto, M. Narazaki, T. Naka, T. Kishimoto. 2000. IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-. J. Immunol. 164:5833.[Abstract/Free Full Text]
11. O’Shea, J. J., M. Gadina, R. D. Schreiber. 2002. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109:(Suppl.):S121.
12. Greenlund, A. C., M. A. Farrar, B. L. Viviano, R. D. Schreiber. 1994. Ligand-induced IFN- receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 13:1591.[Medline]
13. Farrar, M. A., J. D. Campbell, R. D. Schreiber. 1992. Identification of a functionally important sequence in the C terminus of the interferon- receptor. Proc. Natl. Acad. Sci. USA 89:11706.[Abstract/Free Full Text]
14. Oppmann, B., R. Lesley, B. Blom, J. C. Timans, Y. Xu, B. Hunte, F. Vega, N. Yu, J. Wang, K. Singh, et al 2000. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715.[Medline]
15. Parham, C., M. Chirica, J. Timans, E. Vaisberg, M. Travis, J. Cheung, S. Pflanz, R. Zhang, K. P. Singh, F. Vega, et al 2002. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12R1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168:5699.[Abstract/Free Full Text]
16. Robinson, D. S., A. O’Garra. 2002. Further checkpoints in Th1 development. Immunity 16:755.[Medline]

Related articles in The JI:

IN THIS ISSUE

The JI 2003 170: 4879-4880. [Full Text]  

This article has been cited by other articles:

				A. V. Villarino, D. Artis, J. S. Bezbradica, O. Miller, C. J. M. Saris, S. Joyce, and C. A. Hunter IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD Int. Immunol., June 1, 2008; 20(6): 739 - 752. [Abstract] [Full Text] [PDF]

				T. Yoshimoto, N. Morishima, I. Mizoguchi, M. Shimizu, H. Nagai, S. Oniki, M. Oka, C. Nishigori, and J. Mizuguchi Antiproliferative Activity of IL-27 on Melanoma J. Immunol., May 15, 2008; 180(10): 6527 - 6535. [Abstract] [Full Text] [PDF]

				T. Owaki, M. Asakawa, N. Morishima, I. Mizoguchi, F. Fukai, K. Takeda, J. Mizuguchi, and T. Yoshimoto STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production J. Immunol., March 1, 2008; 180(5): 2903 - 2911. [Abstract] [Full Text] [PDF]

				R. K. S. Phoon, A. R. Kitching, D. Odobasic, L. K. Jones, T. J. Semple, and S. R. Holdsworth T-bet Deficiency Attenuates Renal Injury in Experimental Crescentic Glomerulonephritis J. Am. Soc. Nephrol., March 1, 2008; 19(3): 477 - 485. [Abstract] [Full Text] [PDF]

				J. Seita, M. Asakawa, J. Ooehara, S.-i. Takayanagi, Y. Morita, N. Watanabe, K. Fujita, M. Kudo, J. Mizuguchi, H. Ema, et al. Interleukin-27 directly induces differentiation in hematopoietic stem cells Blood, February 15, 2008; 111(4): 1903 - 1912. [Abstract] [Full Text] [PDF]

				M. Huber, V. Steinwald, A. Guralnik, A. Brustle, P. Kleemann, C. Rosenplanter, T. Decker, and M. Lohoff IL-27 inhibits the development of regulatory T cells via STAT3 Int. Immunol., February 1, 2008; 20(2): 223 - 234. [Abstract] [Full Text] [PDF]

				K. D. Mayer, K. Mohrs, W. Reiley, S. Wittmer, J. E. Kohlmeier, J. E. Pearl, A. M. Cooper, L. L. Johnson, D. L. Woodland, and M. Mohrs Cutting Edge: T-bet and IL-27R Are Critical for In Vivo IFN-{gamma} Production by CD8 T Cells during Infection J. Immunol., January 15, 2008; 180(2): 693 - 697. [Abstract] [Full Text] [PDF]

				Y. Cao, P. D. Doodes, T. T. Glant, and A. Finnegan IL-27 Induces a Th1 Immune Response and Susceptibility to Experimental Arthritis J. Immunol., January 15, 2008; 180(2): 922 - 930. [Abstract] [Full Text] [PDF]

				A. Maroof and P. M. Kaye Temporal Regulation of Interleukin-12p70 (IL-12p70) and IL-12-Related Cytokines in Splenic Dendritic Cell Subsets during Leishmania donovani Infection Infect. Immun., January 1, 2008; 76(1): 239 - 249. [Abstract] [Full Text] [PDF]

				J. Siebler, S. Wirtz, C. Frenzel, M. Schuchmann, A. W. Lohse, P. R. Galle, and M. F. Neurath Cutting Edge: A Key Pathogenic Role of IL-27 in T Cell- Mediated Hepatitis J. Immunol., January 1, 2008; 180(1): 30 - 33. [Abstract] [Full Text] [PDF]

				A. Pradhan, Q. T. Lambert, and G. W. Reuther Transformation of hematopoietic cells and activation of JAK2-V617F by IL-27R, a component of a heterodimeric type I cytokine receptor PNAS, November 20, 2007; 104(47): 18502 - 18507. [Abstract] [Full Text] [PDF]

				S. Wang, Y. Miyazaki, Y. Shinozaki, and H. Yoshida Augmentation of Antigen-Presenting and Th1-Promoting Functions of Dendritic Cells by WSX-1(IL-27R) Deficiency J. Immunol., November 15, 2007; 179(10): 6421 - 6428. [Abstract] [Full Text] [PDF]

				J. Pirhonen, J. Siren, I. Julkunen, and S. Matikainen IFN-{alpha} regulates Toll-like receptor-mediated IL-27 gene expression in human macrophages J. Leukoc. Biol., November 1, 2007; 82(5): 1185 - 1192. [Abstract] [Full Text] [PDF]

				T. Yoshimoto, T. Yoshimoto, K. Yasuda, J. Mizuguchi, and K. Nakanishi IL-27 Suppresses Th2 Cell Development and Th2 Cytokines Production from Polarized Th2 Cells: A Novel Therapeutic Way for Th2-Mediated Allergic Inflammation J. Immunol., October 1, 2007; 179(7): 4415 - 4423. [Abstract] [Full Text] [PDF]

				S. Kim, H. S. Kim, K. W. Chung, S. H. Oh, J. W. Yun, S.-H. Im, M.-K. Lee, K.-W. Kim, and M.-S. Lee Essential Role for Signal Transducer and Activator of Transcription-1 in Pancreatic {beta}-Cell Death and Autoimmune Type 1 Diabetes of Nonobese Diabetic Mice Diabetes, October 1, 2007; 56(10): 2561 - 2568. [Abstract] [Full Text] [PDF]

				D. C. Fitzgerald, B. Ciric, T. Touil, H. Harle, J. Grammatikopolou, J. D. Sarma, B. Gran, G.-X. Zhang, and A. Rostami Suppressive Effect of IL-27 on Encephalitogenic Th17 Cells and the Effector Phase of Experimental Autoimmune Encephalomyelitis J. Immunol., September 1, 2007; 179(5): 3268 - 3275. [Abstract] [Full Text] [PDF]

				M. Del Vecchio, E. Bajetta, S. Canova, M. T. Lotze, A. Wesa, G. Parmiani, and A. Anichini Interleukin-12: Biological Properties and Clinical Application Clin. Cancer Res., August 15, 2007; 13(16): 4677 - 4685. [Abstract] [Full Text] [PDF]

				S. F. Yates, A. M. Paterson, K. F. Nolan, S. P. Cobbold, N. J. Saunders, H. Waldmann, and P. J. Fairchild Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation J. Immunol., July 15, 2007; 179(2): 967 - 976. [Abstract] [Full Text] [PDF]

				A. F. Sheibanie, J.-H. Yen, T. Khayrullina, F. Emig, M. Zhang, R. Tuma, and D. Ganea The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23->IL-17 Axis J. Immunol., June 15, 2007; 178(12): 8138 - 8147. [Abstract] [Full Text] [PDF]

				L. M. Johnson and P. Scott STAT1 Expression in Dendritic Cells, but Not T Cells, Is Required for Immunity to Leishmania major J. Immunol., June 1, 2007; 178(11): 7259 - 7266. [Abstract] [Full Text] [PDF]

				Y. Wang, P. H. Dennehy, H. L. Keyserling, K. Tang, J. R. Gentsch, R. I. Glass, and B. Jiang Rotavirus Infection Alters Peripheral T-Cell Homeostasis in Children with Acute Diarrhea J. Virol., April 15, 2007; 81(8): 3904 - 3912. [Abstract] [Full Text] [PDF]

				J. M. Fakruddin, R. A. Lempicki, R. J. Gorelick, J. Yang, J. W. Adelsberger, A. J. Garcia-Pineres, L. A. Pinto, H. C. Lane, and T. Imamichi Noninfectious papilloma virus-like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27 Blood, March 1, 2007; 109(5): 1841 - 1849. [Abstract] [Full Text] [PDF]

				J. Xu and P. D. Drew Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia J. Immunol., February 1, 2007; 178(3): 1904 - 1913. [Abstract] [Full Text] [PDF]

				K.-H. Sonoda, T. Yoshimura, A. Takeda, T. Ishibashi, S. Hamano, and H. Yoshida WSX-1 plays a significant role for the initiation of experimental autoimmune uveitis Int. Immunol., January 1, 2007; 19(1): 93 - 98. [Abstract] [Full Text] [PDF]

				T. Owaki, M. Asakawa, F. Fukai, J. Mizuguchi, and T. Yoshimoto IL-27 Induces Th1 Differentiation via p38 MAPK/T-bet- and Intercellular Adhesion Molecule-1/LFA-1/ERK1/2-Dependent Pathways J. Immunol., December 1, 2006; 177(11): 7579 - 7587. [Abstract] [Full Text] [PDF]

				T. Yoshimura, A. Takeda, S. Hamano, Y. Miyazaki, I. Kinjyo, T. Ishibashi, A. Yoshimura, and H. Yoshida Two-Sided Roles of IL-27: Induction of Th1 Differentiation on Naive CD4+ T Cells versus Suppression of Proinflammatory Cytokine Production Including IL-23-Induced IL-17 on Activated CD4+ T Cells Partially Through STAT3-Dependent Mechanism J. Immunol., October 15, 2006; 177(8): 5377 - 5385. [Abstract] [Full Text] [PDF]

				M. Wittmann, C. Killig, M. Bruder, R. Gutzmer, and T. Werfel Critical involvement of IL-12 in IFN-{gamma} induction by calcineurin antagonists in activated human lymphocytes J. Leukoc. Biol., July 1, 2006; 80(1): 75 - 86. [Abstract] [Full Text] [PDF]

				S. Oniki, H. Nagai, T. Horikawa, J. Furukawa, M. L. Belladonna, T. Yoshimoto, I. Hara, and C. Nishigori Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res., June 15, 2006; 66(12): 6395 - 6404. [Abstract] [Full Text] [PDF]

				M. Shimizu, M. Shimamura, T. Owaki, M. Asakawa, K. Fujita, M. Kudo, Y. Iwakura, Y. Takeda, A. D. Luster, J. Mizuguchi, et al. Antiangiogenic and Antitumor Activities of IL-27. J. Immunol., June 15, 2006; 176(12): 7317 - 7324. [Abstract] [Full Text] [PDF]

				F. Larousserie, P. Charlot, E. Bardel, J. Froger, R. A. Kastelein, and O. Devergne Differential Effects of IL-27 on Human B Cell Subsets J. Immunol., May 15, 2006; 176(10): 5890 - 5897. [Abstract] [Full Text] [PDF]

				M. O Huising, C. P Kruiswijk, and G. Flik Phylogeny and evolution of class-I helical cytokines. J. Endocrinol., April 1, 2006; 189(1): 1 - 25. [Abstract] [Full Text] [PDF]

T. Owaki, M. Asakawa, S. Kamiya, K. Takeda, F. Fukai, J. Mizuguchi, and T. Yoshimoto IL-27 Suppresses CD28-Medicated IL-2 Production through Suppressor of Cytokine Signaling 3. J. Immunol., March 1, 2006; 176(5): 2773 - 2780. [Abstract] [Full Text] [PDF]