Regulation and function of the interleukin 13 receptor alpha 2 during a T helper cell type 2-dominant immune response.
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)alpha2 is a critical down-regulatory factor of IL-13-mediated tissue fibrosis induced by the parasitic helminth Schistosoma mansoni. IL-13Ralpha2 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-13Ralpha2-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-13Ralpha2-deficient mice were treated with a soluble IL-13Ralpha2-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-13Ralpha2 in the down-regulation of a chronic and pathogenic Th2-mediated immune response.
Chiaramonte
Monica G
MG
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Mentink-Kane
Margaret
M
Jacobson
Bruce A
BA
Cheever
Allen W
AW
Whitters
Matthew J
MJ
Goad
Mary E P
ME
Wong
Anthony
A
Collins
Mary
M
Donaldson
Debra D
DD
Grusby
Michael J
MJ
Wynn
Thomas A
TA
D000818:Animals; D015536:Down-Regulation; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology / Q000502:physiology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology*
C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4