Infection-Induced Alterations in Intestinal Critical Role of IL-25 in Nematode

IL-25 (IL-17E) is a member of the IL-17 cytokine family. IL-25–deficient mice exhibit impaired Th2 immunity against nematode infection, implicating IL-25 as a key component in mucosal immunity. The sources of IL-25 and mechanisms responsible for the induction of Th2 immunity by IL-25 in the gastrointestinal tract remain poorly understood. There is also little information on the regulation of IL-25 during inflammation or its role in gut function. In the current study, we investigated the regulation of IL-25 during Nippostrongylus brasiliensis infection and the contribution of IL-25 to the infection-induced alterations in intestinal function. We found that epithelial cells, but not immune cells, are the major source of IL-25 in the small intestine. N. brasiliensis infection-induced upregulation of IL-25 depends upon IL-13 activation of STAT6. IL-25 2/2 mice had diminished intestinal smooth muscle and epithelial responses to N. brasiliensis infection that were associated with an impaired Th2 protective immunity. Exogenous IL-25 induced characteristic changes similar to those after nematode infection but was unable to restore the impaired host immunity against N. brasiliensis infection in IL-13 2/2 mice. These data show that IL-25 plays a critical role in nematode infection-induced alterations in intestinal function that are important for host protective immunity, and IL-13 is the major downstream Th2 cytokine responsible for the IL-25 effects. I nterleukin-25, also called IL-17E, is a cytokine member of the IL-17 family, which includes IL-17A through F. Whereas other members of the IL-17 family have biological activities similar to Th1 inflammatory cytokines, IL-25 appears to be involved primarily in the promotion of Th2 immunity, including allergy, asthma, and enteric nematode infection (1). Of equal importance is that IL-25 also inhibits proinflammatory Th1 and Th17 cytokine responses (2). IL-25 2/2 animals develop severe intestinal inflammation during nematode infection or are highly susceptible to experimental autoimmune encephalomyelitis (3, 4). In addition, IL-25 is downregulated in the colon in patients with inflam-matory bowel disease, and exogenous IL-25 ameliorates experimental colitis in mice (5). Studies in isolated cell populations showed that IL-25 is produced by a variety of immune cells, such as activated Th2 cells (1), mast cells (6), macrophages (7), and CD4 + and CD8 + T cells (2). More recently, it was demonstrated that peripheral human eosinophils and basophils secrete IL-25 (8). There is a low constitutive expression of IL-25 in several tissues, with the highest expression in gastrointestinal tract, lung, and testis (1). IL-25 mRNA is upregulated …