Regulation and function of the interleukin 13 receptor α 2 during a T helper cell type 2–dominant immune response

MG Chiaramonte, M Mentink-Kane… - The Journal of …, 2003 - rupress.org
MG Chiaramonte, M Mentink-Kane, BA Jacobson, AW Cheever, MJ Whitters, MEP Goad…
The Journal of experimental medicine, 2003rupress.org
Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they
are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms
that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of
T helper cell (Th) 2-dominant immune responses, exhibiting a diverse array of functional
activities including regulation of airway hyperreactivity, resistance to nematode parasites,
and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R) α2 is a critical …
Highly polarized type 2 cytokine responses can be harmful and even lethal to the host if they are too vigorous or persist too long. Therefore, it is important to elucidate the mechanisms that down-regulate these reactions. Interleukin (IL)-13 has emerged as a central mediator of T helper cell (Th)2-dominant immune responses, exhibiting a diverse array of functional activities including regulation of airway hyperreactivity, resistance to nematode parasites, and tissue remodeling and fibrosis. Here, we show that IL-13 receptor (R)α2 is a critical down-regulatory factor of IL-13–mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13Rα2 expression was induced after the onset of the fibrotic response, IL-10, IL-13, and Stat6 dependent, and inhibited by the Th1-inducing adjuvant IL-12. Strikingly, schistosome-infected C57BL/6 and BALB/c IL-13Rα2–deficient mice showed a marked exacerbation in hepatic fibrosis, despite displaying no change in granuloma size, tissue eosinophilia, or mastocytosis. Fibrosis increased despite the fact that IL-13 levels decreased significantly in the liver and serum. Importantly, pathology was prevented when IL-13Rα2–deficient mice were treated with a soluble IL-13Rα2-Fc construct, formally demonstrating that their exacerbated fibrotic response was due to heightened IL-13 activity. Together, these studies illustrate the central role played by the IL-13Rα2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response.
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