IL-10 Is Required for Prevention of Necrosis in the Small Intestine and Mortality in Both Genetically Resistant BALB/c and Susceptible C57BL/6 Mice Following Peroral Infection withToxoplasma gondii

Abstract

The role for IL-10 in the immunopathogenesis of acute toxoplasmosis following peroral infection was examined in both genetically susceptible C57BL/6 and resistant BALB/c mice. C57BL/6-background IL-10-targeted mutant (IL-10−/−) mice all died in 2 wk after infection with 20 cysts of the ME49 strain, whereas only 20% of control mice succumbed. Histological studies revealed necrosis in the small and large intestines and livers of infected IL-10−/− mice. The necrosis in the small intestine was the most severe pathologic response and was not observed in control mice. Treatment of infected IL-10−/− mice with either anti-CD4 or anti-IFN-γ mAb prevented intestinal pathology and significantly prolonged time to death. Treatment of these animals with anti-IL-12 mAb also prevented the pathology. Significantly greater amounts of IFN-γ mRNA were detected in the lamina propria lymphocytes obtained from the small intestine of infected IL-10−/− mice than those from infected control mice. In common with C57BL/6-background IL-10−/− mice, BALB/c-background IL-10−/− mice all died developing intestinal pathology after infection. Control BALB/c mice all survived even after infection with 100 cysts and did not develop the intestinal lesions. Treatment with anti-IFN-γ mAb prevented the pathology and prolonged time to death of the infected IL-10−/− mice. These results strongly suggest that IL-10 plays a critical role in down-regulating IFN-γ production in the small intestine following sublethal peroral infection with Toxoplasma gondii and that this down-regulatory effect of IL-10 is required for prevention of development of IFN-γ-mediated intestinal pathology and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice.

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4+ T cells

“…IL-10 is an important regulatory cytokine that controls the inflammatory process [8,24]. This molecule is produced by P IEL, but does not appear to play an essential role in the regulatory process mediated by P IEL in this model system, since P IEL isolated from IL-10 -/-mice remain protective following transfer.…”

Partial depletion of CD4+CD25+Foxp3+ T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice

“…Peyer's patches (PP) were excised from the small intestine and gently crushed to obtain single cell suspensions. The previously described method [27] with minor modifications was used to obtain intestinal cells. Briefly, the small intestine was cut into 5e10 cm pieces and further cut longitudinally to expose the inner luminal surface of the intestine, incubated in 0.14 mg/ml 1,4,-dithioerythritol (Sigma Aldrich, Bornem, Belgium) and agitated for 15 min at 37 C to obtain a suspension of intestinal epithelial (IE) cells.…”

IL‐33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii

“…Cytokines regulating type-1 responses such as IL-4 and IL-10 have been reported to be involved in limiting the potentially damaging type-1 response to T. gondii [27,29,[37][38][39][40][41]. Although our study shows no differences in IL-4 and IL-10 expression, which could account for the increase in susceptibility of T1/ST2 À/À mice to TE, we did demonstrate a consistent, albeit non-significant, reduction in the expression of IL-13 in these animals over a number of experiments.…”

“…Furthermore, production of iNOS, TNF-a and IFN-g in the brain are named as a mechanism in pathophysiology of a number of central nervous system diseases [30][31][32]. Although IFN-g is widely regarded as the central cytokine in protective immunity to the parasite [33][34][35][36], excess production of this cytokine can be detrimental during T. gondii infection resulting in damaging immunopathology [33,[36][37][38].…”

“…Furthermore, production of iNOS, TNF-a and IFN-g in the brain are named as a mechanism in pathophysiology of a number of central nervous system diseases [30][31][32]. Although IFN-g is widely regarded as the central cytokine in protective immunity to the parasite [33][34][35][36], excess production of this cytokine can be detrimental during T. gondii infection resulting in damaging immunopathology [33,[36][37][38].Cytokines regulating type-1 responses such as IL-4 and IL-10 have been reported to be involved in limiting the potentially damaging type-1 response to T. gondii [27,29,[37][38][39][40][41]. Although our study shows no differences in IL-4 and IL-10 expression, which could account for the increase in susceptibility of T1/ST2 À/À mice to TE, we did demonstrate a consistent, albeit non-significant, reduction in the expression of IL-13 in these animals over a number of experiments.…”