IL-10 Regulates Liver Pathology in Acute Murine<i>Schistosomiasis mansoni</i>But Is Not Required for Immune Down-Modulation of Chronic Disease

Wynn, Thomas A.; Cheever, Allen W.; Williams, Megan E.; Hieny, Sara; Caspar, Patricia; Kühn, Ralf; Müller, Werner; Sher, Alan

doi:10.4049/jimmunol.160.9.4473

Cited by 147 publications

(3 citation statements)

References 38 publications

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“…tuberculosis growth [ 38 ]. In Schistosomiasis mansoni infection, a lack of IL-10 caused dysregulated Th1 responses, resulting in aggravated granulomatous inflammation and an increased mortality in the acute phase [ 39 ]. In C. trachomatis respiratory infection, IL-10 was reported to inhibit the priming and expansion of Th1 responses and contribute to the fibrotic reaction following infection [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

IL-27 Signaling Promotes Th1 Response by Downregulating IL-10 Production in DCs during Chlamydial Respiratory Infection

et al. 2023

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Chlamydia trachomatis usually causes mucosal infections, bringing considerable morbidity and socioeconomic burden worldwide. We previously revealed that IL-27/IL-27R mediates protection against chlamydial invasion by promoting a protective Th1 response and suppressing neutrophilic inflammation. Here, we used the mouse model of Chlamydia muridarum (C. muridarum) respiratory infections to further investigate the impact of IL-27 signaling in the DCs-regulated immune response, since an elevated IL-27/IL-27R expression in DCs was identified following chlamydial infection. An adoptive transfer of Chlamydia muridarum-stimulated DCs to wild-type mice approach was subsequently used, and the donor-DCs-promoted resistance with a higher Th1 response against chlamydial infection was attenuated when DCs lacking IL-27R were used as donor cells. Flow cytometry analysis revealed the suppression of IL-27 signaling on DCs phenotypic maturation. A further functional maturation analysis of DCs revealed that IL-27 signaling restricted the protein and mRNA expression of IL-10 from DCs following infection. Thus, these findings suggest that IL-27 signaling could support the Th1 response via inhibiting IL-10 production in DCs, thus mediating the protective host defense against chlamydial respiratory infection.

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Section: Discussionmentioning

confidence: 99%

IL-27 Signaling Promotes Th1 Response by Downregulating IL-10 Production in DCs during Chlamydial Respiratory Infection

et al. 2023

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“…Thus, treatment of schistosome-infected mice with exogenous IL-10 has been shown to directly regulate cellular responses and reduce immunopathological damage (39,40). Additionally, Wynn and colleagues (26) have demonstrated that in the absence of IL-10 (IL-10-deficient mice) there is an elevated type 1 cytokine profile with impaired granuloma formation and increased pathology during acute schistosome infection. In double IL-10-and IL-4-deficient or IL-10-and IL-12-deficient animals the central regulatory role for IL-10 in responses to schistosome eggs has been further delineated (41).…”

Section: Discussionmentioning

confidence: 99%

“…Cells were restimulated with anti-CD3. IFN-␥ and IL-4 in cell supernatants were assayed as respective representative type 1 and type 2 cytokines; we also measured IL-10, as this cytokine has been shown to regulate type 1 responses during acute schistosome infection (25,26). CD3-stimulated cells from normal infected mice displayed IFN-␥ secretion and limited IL-4 secretion when examined 28 days after infection; later during infection this response was superseded by a type 2 dominated response, with reduced IFN-␥ production and marked enhanced secretion of IL-4 (Fig.…”

Section: Failure Of Egg-tolerized Mice To Down-modulate Type 1 Respon...mentioning

confidence: 99%

Tolerization of Mice toSchistosoma mansoniEgg Antigens Causes Elevated Type 1 and Diminished Type 2 Cytokine Responses and Increased Mortality in Acute Infection

Fallon

Dunne

1999

The Journal of Immunology

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The granuloma that surrounds the Schistosoma mansoni egg is the cause of pathology in murine schistosomiasis, and its formation is driven by egg Ag-stimulated type 1 and type 2 cytokines. To determine the role of egg-driven immune responses during schistosome infection we rendered CBA/Ca mice unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy. In the early acute stages of schistosome infection, egg-tolerized mice suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limited granuloma responses were detected in the intestines of these mice, and this was associated with a >90% reduction in egg excretion. Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis. Elevated plasma transaminase levels confirmed the damage to hepatocytes. Infected egg-tolerized mice had impaired proliferation responses to egg Ag but intact responses to worm Ag. Tolerized mice had diminished Ab responses to egg Ag and had a type 1 cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mice failed to down-regulate type 1 cytokines that are normally elicited during early schistosome infection. Hepatic granuloma cells from egg-tolerized mice were also type 1 cytokine dominated, with elevated frequencies of Tc1/Th1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized to schistosome eggs have elevated type 1 cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host.

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IL‐10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni

et al. 2003

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After infection of mice with Schistosoma mansoni, deposition of eggs in the walls of the intestine and liver provokes an intense (acute) T cell response that peaks at week 8 and, thereafter, down-modulates as the disease becomes chronic. Egg antigen-stimulated proliferation of mesenteric lymph node and spleen cells in vitro was intense at week 8 in both IL-10 -/-and wild-type (WT) mice, while proliferative responses were markedly reduced at week 15 in WT mice, but undiminished in IL-10 -/-animals. Moreover, in the absence of IL-10 production, levels of both IFN-+ and IL-4 remained elevated at week 15. Granulomas around eggs embolized in the livers of WT mice were significantly smaller at week 15 than week 8, whereas those in IL-10 -/-animals were larger at week 8, showed no reduction in size at week 15, and were less sharply demarcated by peripheral collagen. There was also a greater leukocytic infiltration and necrosis of the hepatic parenchyma. These data suggest that in mice IL-10 regulates not only the intensity of hepatic inflammation, but also granuloma organization and cohesiveness. It is a crucial agent in the down-modulation of immune responses and immunopathology that defines the transition from acute to chronic disease.

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IL-10 Regulates Liver Pathology in Acute MurineSchistosomiasis mansoniBut Is Not Required for Immune Down-Modulation of Chronic Disease

Cited by 147 publications

References 38 publications

IL-27 Signaling Promotes Th1 Response by Downregulating IL-10 Production in DCs during Chlamydial Respiratory Infection

IL-27 Signaling Promotes Th1 Response by Downregulating IL-10 Production in DCs during Chlamydial Respiratory Infection

Tolerization of Mice toSchistosoma mansoniEgg Antigens Causes Elevated Type 1 and Diminished Type 2 Cytokine Responses and Increased Mortality in Acute Infection

IL‐10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni

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