The cytokine interleukin (IL) 25 has been implicated in the initiation of type 2 immunity by driving the expression of type 2 cytokines such as IL-5 and IL-13, although its role in the regulation of immunity and infection-induced inflammation is unknown. Here, we identify a dual function for IL-25: first, in promoting type 2 cytokine-dependent immunity to gastrointestinal helminth infection and, second, in limiting proinflammatory cytokine production and chronic intestinal inflammation. Treatment of genetically susceptible mice with exogenous IL-25 promoted type 2 cytokine responses and immunity to Trichuris. IL-25 was constitutively expressed by CD4+ and CD8+ T cells in the gut of mouse strains that are resistant to Trichuris, and IL-25–deficient mice on a genetically resistant background failed to develop a type 2 immune response or eradicate infection. Furthermore, chronically infected IL-25−/− mice developed severe infection-induced intestinal inflammation associated with heightened expression of interferon-γ and IL-17, identifying a role for IL-25 in limiting pathologic inflammation at mucosal sites. Therefore, IL-25 is not only a critical mediator of type 2 immunity, but is also required for the regulation of inflammation in the gastrointestinal tract.

Gastrointestinal (GI) nematode infections are an important public health and economic concern. Experimental studies have shown that resistance to infection requires CD4 ؉ T helper type 2 (Th2) cytokine responses characterized by the production of IL-4 and IL-13. However, despite >30 years of research, it is unclear how the immune system mediates the expulsion of worms from the GI tract. Here, we demonstrate that a recently described intestinal goblet cell-specific protein, RELM␤͞FIZZ2, is induced after exposure to three phylogenetically distinct GI nematode pathogens. Maximal expression of RELM␤ was coincident with the production of Th2 cytokines and host protective immunity, whereas production of the Th1 cytokine, IFN-␥, inhibited RELM␤ expression and led to chronic infection. Furthermore, whereas induction of RELM␤ was equivalent in nematode-infected wild-type and IL-4-deficient mice, IL-4 receptor-deficient mice showed minimal RELM␤ induction and developed persistent infections, demonstrating a direct role for IL-13 in optimal expression of RELM␤. Finally, we show that RELM␤ binds to components of the nematode chemosensory apparatus and inhibits chemotaxic function of a parasitic nematode in vitro. Together, these results suggest that intestinal goblet cell-derived RELM␤ may be a novel Th2 cytokine-induced immune-effector molecule in resistance to GI nematode infection.

We have investigated the influence of mast cells on the barrier function of intestinal epithelium during nematode infection. Trichinella spiralis infection induces a strong type 2 cytokinemediated inflammation, resulting in a critical mucosal mastocytosis that is known to mediate expulsion of the parasites from the intestine. The host response to infection is also characterized by an increase in mucosal leakiness. We show here that intestinal epithelial permeability is markedly elevated during infection, with kinetics that mirror the adaptive immune response to primary and secondary infection. Furthermore, we have identified degradation of the tight junction protein, occludin, thereby providing a mechanism for increased paracellular permeability during helminth infection. We further demonstrate by using anti-c-kit antibody and IL-9 transgenic mice that mast cells are directly responsible for increasing epithelial paracellular permeability and that mice deficient in a mast cell-specific protease fail to increase intestinal permeability and fail to expel their parasite burden. These results provide the mechanism whereby mucosal mast cells mediate parasite expulsion from the intestine.T he adult stage of the nematode Trichinella spiralis resides within enterocytes of the jejunum. During parasite infection characteristic changes occur in the small intestine (1). It has long been known that the gut becomes edematous and inflamed, with these responses peaking at the time of parasite expulsion from the host, but the precise mechanisms involved have remained obscure. Infection induces leakiness in the intestinal epithelium that is considered to be a host defense mechanism against the parasite (the leak-lesion hypothesis) (2).We hypothesize that an increase in epithelial paracellular permeability resulting in the loss of parasites is a direct consequence of adaptive immunity. T. spiralis elicits a strong T helper 2 response resulting in intestinal goblet cell hyperplasia, eosinophilia, and a profound mucosal mastocytosis (3-5). Efficient parasite expulsion depends on CD4 ϩ T cells through control of the critical mast cell response (6). In the absence of intestinal mast cells the loss of parasites is markedly delayed (7). The mechanism by which mast cells induce parasite expulsion is unknown and is the focus of this study.Changes in epithelial paracellular permeability during the course of T. spiralis infection in mice and the role that the mast cell may play in inducing these changes were investigated. By depleting mast cells with anti-c-kit antibodies or by using IL-9 transgenic mice that overexpress mast cells (8), we present compelling evidence that mast cells are the key mediators of increased mucosal permeability. To understand further the action of mast cells on intestinal epithelium, we have infected mice deficient in mouse mast cell protease-1 (mMCP-1) that had been shown previously to delay parasite expulsion (9) and investigated whether this mast cell-specific proteinase is involved in increased epithelial perm...

Expulsion of gastrointestinal nematodes is associated with pronounced mucosal mast cell (MMC) hyperplasia, differentiation, and activation, accompanied by the systemic release of MMC granule chymases (chymotrypsin-like serine proteases). The β-chymase mouse mast cell protease-1 (mMCP-1) is expressed predominantly by intraepithelial MMCs, and levels in the bloodstream and intestinal lumen are maximal at the time of worm expulsion in parasitized mice. To address the in vivo functions of MMC-specific β-chymases, we have generated transgenic mice that lack the mMCP-1 gene. They were backcrossed onto a congenic BALB/c background to investigate the response to nematode infection. The deletion of the mMCP-1 gene is associated with significantly delayed expulsion of Trichinella spiralis and increased deposition of muscle larvae in BALB/c mice despite the presence of normal and sometimes increased numbers of MMCs. Neither worm fecundity nor worm burdens were altered in Nippostrongylus-infected mMCP-1−/− BALB/c mice. These data demonstrate, for the first time, that the ablation of an MMC-derived effector molecule compromises the expulsion process.