Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis.

Abstract

In several allergic, autoimmune, and infectious diseases, fibrosis is a major cause of morbidity and mortality. Here, using a model of infection-induced liver fibrosis, we show that interleukin (IL)-13 is required at all stages of Schistosomiasis mansoni infection to induce fibrosis. IL-4 production was preserved in IL-13-deficient mice, yet failed to significantly contribute to the fibrotic response in either acute or chronic infection. Significant fibrosis develops in all infected mice, although the magnitude of the response varies widely in inbred mice. C3H/HeN, BALB/c, and C57BL/6 mice develop high, intermediate, and low levels of fibrosis, respectively. Despite these differences, IL-13 antagonism resulted in a marked amelioration of fibrosis in all strains. The fibrotic mechanism in the high- and low-responder strains was unrelated to their tissue eosinophil or mast cell responses, but did correlate with their patterns of IL-13, IL-10, and interferon gamma (IFN-gamma) mRNA expression. Indeed, severe fibrosis correlated with a high IL-13 and low IFN-gamma/IL-10 mRNA response. Because fibrotic diseases are typically progressive disorders, an important issue was to determine whether IL-13 inactivation might be used to treat an established and ongoing fibrotic disease. Here, IL-13 antagonism was highly efficacious, even after fibrosis and the Th2 cytokine response were firmly established. These studies demonstrate the central role played by IL-13 in fibrogenesis and suggest that therapeutic approaches aimed at disrupting the IL-13 pathway will be highly effective at preventing fibrotic disease caused by chronic Th2-mediated inflammatory reactions.

• Authors: M G Chiaramonte, A W Cheever, J D Malley, D D Donaldson, T A Wynn
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 34 Issue 2 Pg. 273-82 (Aug 2001) ISSN: 0270-9139 [Print] United States
• PMID: 11481612 (Publication Type: Journal Article)

Chemical References

• Il13ra1 protein, mouse
• Immunoglobulin Fc Fragments
• Interleukin-13
• Interleukin-13 Receptor alpha1 Subunit
• RNA, Messenger
• Receptors, Interleukin
• Receptors, Interleukin-13
• Interleukin-10
• Interferon-gamma

Topics

• Animals
• Chronic Disease
• Disease Progression
• Female
• Immunoglobulin Fc Fragments (pharmacology)
• Interferon-gamma (genetics)
• Interleukin-10 (genetics)
• Interleukin-13 (antagonists & inhibitors, deficiency, genetics, physiology)
• Interleukin-13 Receptor alpha1 Subunit
• Liver (metabolism)
• Liver Cirrhosis (drug therapy, parasitology, physiopathology, prevention & control)
• Mice
• Mice, Inbred Strains
• RNA, Messenger (metabolism)
• Receptors, Interleukin (chemistry)
• Receptors, Interleukin-13
• Schistosomiasis mansoni (complications)