Modulation of Intestinal Muscle Contraction by Interleukin-9 (IL-9) or IL-9 Neutralization: Correlation with Worm Expulsion in Murine Nematode Infections

Abstract

Immune responses associated with intestinal nematode infections are characterized by the activation of T-helper 2 (Th2) cells. Previous studies demonstrated that duringTrichinella spiralis infection, Th2 cells contribute to the development of intestinal muscle hypercontractility and to worm eviction from the gut, in part through signal transducer and activator of transcription factor 6 (Stat6). Interleukin-9 (IL-9), a Th2-cellderived cytokine, has pleiotropic activities on various cells that are not mediated through Stat6. In this study, we investigated the role of IL-9 in the generation of enteric muscle hypercontractility in mice infected with the intestinal parasite T. spiralis and the cecal parasite Trichuris muris. Treatment of mice with IL-9 enhanced infection-induced jejunal muscle hypercontractility and accelerated worm expulsion in T. spiralis infection. These effects were associated with an up-regulation of IL-4 and IL-13 production from in vitro-stimulated spleen cells. In addition, increases in the level of intestinal goblet cells and in the level of mouse mucosal mast cell protease 1 (MMCP-1) in serum were observed in infected mice following IL-9 administration. However, the neutralization of IL-9 by anti-IL-9 vaccination or by anti-IL-9 antibody had no significant effect on worm expulsion or muscle contraction in T. spiralis-infected mice. In contrast, the neutralization of IL-9 significantly attenuated T. muris infection-induced colonic muscle hypercontractility and inhibited worm expulsion. The attenuated expulsion of the parasite by IL-9 neutralization was not accompanied by changes in goblet cell hyperplasia or the MMCP-1 level. These findings suggest that IL-9 contributes to intestinal muscle function and to host protective immunity and that its importance and contribution may differ depending on the type of nematode infection.

IL-9 Promotes IL-13-Dependent Paneth Cell Hyperplasia and Up-Regulation of Innate Immunity Mediators in Intestinal Mucosa

“…In this model, mast cells increase epithelial permeability by producing proteases such as mMCP-1, a process promoted by IL-9 (24,36). Other antinematode effector mechanisms modulated by IL-9 or IL-13 include increased epithelial cell turnover acting like an epithelial escalator to expel Trichuris parasites (11) and jejunal muscle hypercontractility (37). Paneth cell hyperplasia has also been reported during T. spiralis infection, and this process seemed T cell-dependent (13), but the role of IL-9 and IL-13 in this process had not been described so far.…”

Immunity to gastrointestinal nematode infections

“…99 As a result, T. muris and H. polygyrus expulsion are impaired in mast cell-deficient mice 99,100 as well as upon administration of neutralizing IL-9 antibodies, 101,102 although it should be noted that studies using mast celldeficient mice (c-kit mutants) suffer from possible confounding factors given the role for c-kit on many other cell types, and thus remain to be clarified. Interestingly, a recent study also found that mast cells not only can respond to IL-33 but might also enhance the transmission of type 2 signals by the production of IL-33 in response to adenosine triphosphate release by dying epithelial cells.…”

“…Thus, the responsiveness of smooth muscle cells to neurotransmitters that control contraction via muscarinic receptors are important for N. brasiliensis expulsion. 193 Most of the available data on gut peristalsis during nematode infection are however highly correlative 73,102 and its importance remains to be established. Nevertheless, together these mechanisms effectively expel the invading parasite.…”

Development of an anti‐IL‐12 p40 auto‐vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection

“…Both biochemical and genetic procedures have been used to produce these vaccines. Chemical coupling of mouse IL-9 to OVA produced very immunogenic complexes leading to inhibition of IL-9 function in immunized mice, which resulted in their failure to expel the nematode Trichuris muris and interfered with intestinal muscle contraction [8,10]. Positive results have [DOI 10.1002/eji.200425443] also been reported after immunization with mouse TNF-a fused to an OVA helper sequence [7], with a DNA vaccine comprising a tetanus toxoid sequence inserted into DNA encoding IL-5 [11] or with a vaccine based on virus-like particles (VLP) incorporating mouse TNF-a peptides into papillomavirus VLP [12].…”