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Infection and Immunity, March 2006, p. 1471-1479, Vol. 74, No. 3
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.3.1471-1479.2006

Interleukin-5 (IL-5) Augments the Progression of Liver Fibrosis by Regulating IL-13 Activity

Rachael M. Reiman,1 Robert W. Thompson,1 Carl G. Feng,2 Danielle Hari,1 Rachel Knight,1 Allen W. Cheever,3 Helene F. Rosenberg,4 and Thomas A. Wynn1*

Immunopathogenesis,1 Immunobiology Sections, Laboratory of Parasitic Diseases,2 Eosinophil Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-8003,4 Biomedical Research Institute, Rockville, Maryland 208523

Received 11 October 2005/ Returned for modification 23 November 2005/ Accepted 28 November 2005

Eosinophils are frequently found in increased numbers in a variety of chronic fibrotic diseases; however, their role in the development of hepatic fibrosis has not been dissected in vivo. Here, we used interleukin-5 (IL-5) knockout (KO) mice to determine whether eosinophils contribute to the progressive liver fibrosis that develops in response to chronic Schistosoma mansoni infection. Although infection intensities were similar in C57BL/6 and IL-5 KO mice, the average size of granulomas was significantly smaller in both acutely and chronically infected IL-5 KO mice. Their granulomas were also completely devoid of eosinophils. In addition, the knockout mice displayed over a 40% reduction in hepatic fibrosis by week 16 postinfection. The reduced fibrosis was associated with increased production of the antifibrotic cytokine gamma interferon. Moreover, although IL-13 production did not decrease consistently in the absence of IL-5, IL-13-triggered responses were substantially reduced in the granulomatous tissues. This was confirmed by analyzing the expression of several genes associated with alternative macrophage activation, including arginase 1, Fizz-1, and YM-1. Importantly, all of these IL-13-regulated genes have been linked with the mechanisms of wound healing and fibrosis. In addition to IL-5 polarizing the antigen-specific CD4+ Th2 cell response, we found that granuloma eosinophils were themselves a significant source of IL-13. Thus, by producing profibrotic mediators and polarizing the Th2 response, these findings illustrate both direct and indirect roles for eosinophils and IL-5 in the pathogenesis of schistosomiasis-induced liver fibrosis. Thus, inhibiting the activity of IL-5 or eosinophils may prove effective for a variety of chronic fibrotic diseases.

* Corresponding author. Mailing address: 50 South Drive, Rm. 6154, MSC 8003, Bethesda, MD 20892-8003. Phone: (301) 496-4758. Fax: (301) 480-5025. E-mail: twynn{at}niaid.nih.gov.

Editor: J. F. Urban, Jr.

Infection and Immunity, March 2006, p. 1471-1479, Vol. 74, No. 3
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.3.1471-1479.2006




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