A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production.
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-beta, IL-6, and IL-23 have increased mRNA and protein expression of IL-13R alpha1 and mRNA expression of IL-4R alpha 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-gammaT, 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-gamma 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-gammaT 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.
Newcomb
Dawn C
DC
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Zhou
Weisong
W
Moore
Martin L
ML
Goleniewska
Kasia
K
Hershey
Gurjit K K
GK
Kolls
Jay K
JK
Peebles
R Stokes
RS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006131:Growth Inhibitors / Q000502:physiology*; D018793:Interleukin-13 / Q000502:physiology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053660:Receptors, Interleukin-13 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D006131:Growth Inhibitors; D018793:Interleukin-13; D020381:Interleukin-17; D053660:Receptors, Interleukin-13