Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris

Abstract

Upon infection with the cecum-dwelling nematode Trichuris muris, the majority of inbred strains of mice launch a Th2-type immune response and in doing so expel the parasite before patency. In contrast, there are a few mouse strains which develop a nonprotective Th1-type response resulting in a chronic infection and the presence of adult worms. Of the Th2 cytokines known to be associated with the resistant phenotype (interleukin-4 [IL-4], IL-5, IL-9, and IL-13), comparatively little is known about the contribution that IL-9 makes towards the protective immune response. In this study we demonstrate that IL-9 is expressed early during the Th2-type response and that its elevation in vivo results in the enhancement of intestinal mastocytosis and the production of both the immunoglobulin E (IgE) and IgG1 isotypes. In addition, elevated IL-9 levels in vivo facilitated the loss of T. muris from the intestine. That IL-9 is important in promoting worm expulsion was also seen following infection of IL-9-transgenic mice, which constitutively overexpress the cytokine. These animals displayed an extremely rapid, but immune mediated, expulsion of the parasite. Also evident in these animals was a pronounced intestinal mastocytosis, which was previously shown by us to be responsible for the expulsion of the related nematode Trichinella spiralis from these animals. Taken together with observations of IL-9 production following infection with other helminths, the results imply that IL-9 contributes to the general mast cell and IgE response characteristic of these infections and, more specifically, enhances resistance to T. muris.

FIG. 1

Kinetics of IL-9 and IL-4 gene expression in the MLN following infection of BALB/K (a) and AKR (b) mice with T. muris. Values were individually normalized to those for the HPRT gene and are expressed relative to those for uninfected control animals, which were arbitrarily given a value of 1.

FIG. 2

Effects of manipulating host IL-9 levels in AKR mice through the administration of an IL-9 complex following infection with T. muris. (a) Mean numbers of intestinal mast cells per 20 CCU ± SE. (b and c) Levels of parasite-specific IgG1 (b) and IgG2a (c) in serum, expressed as the mean optical density (OD) ± SE against dilution of serum. (d) Mean adult worm burden ± SE. *, stunted damaged worms; NS, not significant. All values were determined on day 35 p.i.

FIG. 3

Effects of manipulating host IL-9 levels in C57BL/6 mice through the administration of TS1.G6, an IL-9-secreting T-cell line, following infection with T. muris. (a) Mean worm burden ± SE. (b) Levels of total IgE in serum, expressed as means ± SE. (c) Mean numbers of intestinal mast cells per 20 CCU ± SE. (d) Levels of MMCP-1 in serum, expressed as means ± SE. All values were determined on day 17 p.i.

FIG. 4

Infection of IL-9-transgenic (TG) and wild-type (WT) mice with T. muris. (a and b) Levels of parasite-specific IgG1 (a) and IgG2a (b) on day 34 p.i., expressed as mean optical density (OD) ± SE against dilution of serum. (c) Mean numbers of intestinal mast cells per 20 CCU ± SE throughout infection. (d) Levels of MMCP-1 in serum throughout infection, expressed as means ± SE.

FIG. 5

Effects of cortisone treatment on IL-9-transgenic (TG) and wild-type (WT) animals. (a) Mean worm burden ± SE on day 12 p.i. (b) Levels of parasite-specific IgG1 in serum in IL-9 transgenic mice on day 34 p.i., expressed as mean optical density (OD) ± SE against dilution of serum.