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A Functional IL-13 Receptor Is Expressed on Polarized Murine CD4⁺ Th17 Cells and IL-13 Signaling Attenuates Th17 Cytokine Production¹

Dawn C. Newcomb^*, Weisong Zhou^*, Martin L. Moore, Kasia Goleniewska^*, Gurjit K. K. Hershey, Jay K. Kolls and R. Stokes Peebles, Jr.^2,*

^* Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Pediatrics, Emory University, Atlanta, GA 30322; Department of Pediatrics, Cincinnati Children’s Hospital, Cincinnati, OH 45229; and Department of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213

IL-17A is produced from Th17 cells, and is involved in many autoimmune and inflammatory diseases. IL-13R has not previously been reported to be functionally expressed on T cells; however, we found that purified BALB/c CD4⁺ cells polarized to Th17 with TGF-β, IL-6, and IL-23 have increased mRNA and protein expression of IL-13R1 and mRNA expression of IL-4R compared with Th0, Th1, or Th2 polarized cells. The addition of IL-13 at Th17 polarization negatively regulated IL-17A and IL-21 expression, and reduced the number of CD4⁺ T cells producing IL-17A. Further, adding IL-13 at the time of Th17 cell restimulation attenuated IL-17A expression. CD4⁺ Th17 polarized cells from IL-4 knockout (KO) mice also had IL-13-induced inhibition of IL-17A production, but this was not observed in IL-4R KO and STAT6 KO mice. Addition of IL-13 at polarization increased IL-13R expression in wild-type Th17 cells. Further, IL-13 administration during Th17 polarization down-regulated retinoic acid-related-T, the transcription required for Th17 development; increased STAT6 phosphorylation, and up-regulated GATA3, the transcription factor activated during the development of Th2 cells. This IL-13-mediated effect was specific to Th17 cells as IL-13 neither decreased IFN- expression by Th1 cells nor affected Th2 cell production of IL-4. Collectively, we have shown that Th17 cells express a functional IL-13R and that IL-13 negatively regulates IL-17A and IL-21 production by decreasing retinoic acid-related-T expression and while increasing phosphorylation of STAT6 and GATA3 expression. Therefore, therapeutic intervention inhibiting IL-13 production could have adverse consequences by up-regulating Th17 inflammation in certain disease states.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health: F32HL091653, R01 HL090664, R01AI070672, R01AI054660, R01HL069449, R01AI059108, and GM 015431.

² Address correspondence and reprint requests to Dr. R. Stokes Peebles, Jr., 1161 21^st Avenue, T-1221 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail address: Stokes.peebles{at}vanderbilt.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalitis; KO, knockout; ROR, retinoic acid-related.

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The JI 2009 182: 5157-5158. [Full Text]