IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-12

Self Cite

108

IL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19−/− mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-γ production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35−/− mice (lacking IL-12), p35/19−/− mice (lacking IL-12 and IL-23), p35/40−/− mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A−/− mice (lacking IL-12 and IL-17A). We found survival of p35−/− and p35/IL-17A−/− mice, whereas p35/19−/− and p35/40−/− mice died within 3–6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35−/− mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.

Section: In the Absence Of Il-12 Il-23 But Not (P40) 2 Provides Psupporting

confidence: 63%

Section: Discussionmentioning

confidence: 79%

Protective Immunity to Systemic Infection with AttenuatedSalmonella entericaserovar Enteritidis in the Absence of IL-12 Is Associated with IL-23-Dependent IL-22, but Not IL-17

Schulz

Köhler

Schütze

et al. 2008

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108

“…That this compensatory response is unable to control experimental infection (7) indicates that the IL-23-induced IFN-␥ response is not as potent as the IL-12p70-induced response, and our data demonstrate that the total number of Ag-specific CD4 T cells is significantly reduced when only IL-23 is available. A similar ability of IL-23 to compensate for the absence of IL-12p70 has been reported for the Toxoplasma model, in which exogenous IL-23 was able to improve control of pathogen burden in IL-12p40-deficient mice (33). That a compensatory IL-23 response may protect humans from Tb is suggested by the fact that although there are extensive reports of increased susceptibility to mycobacterial infection in humans lacking IL-12p40 or IL-12R␤1 (34 -38), there are no reports of susceptibility in humans lacking IL-12p35.…”

Section: Discussionmentioning

confidence: 65%

IL-23 Compensates for the Absence of IL-12p70 and Is Essential for the IL-17 Response during Tuberculosis but Is Dispensable for Protection and Antigen-Specific IFN-γ Responses if IL-12p70 Is Available

Khader

Pearl

Sakamoto

et al. 2005

425

463

IL-12p70 induced IFN-γ is required to control Mycobacterium tuberculosis growth; however, in the absence of IL-12p70, an IL-12p40-dependent pathway mediates induction of IFN-γ and initial bacteriostatic activity. IL-23 is an IL-12p40-dependent cytokine containing an IL-12p40 subunit covalently bound to a p19 subunit that is implicated in the induction of CD4 T cells associated with autoimmunity and inflammation. We show that in IL-23 p19-deficient mice, mycobacterial growth is controlled, and there is no diminution in either the number of IFN-γ-producing Ag-specific CD4 T cells or local IFN-γ mRNA expression. Conversely, there is an almost total loss of both IL-17-producing Ag-specific CD4 T cells and local production of IL-17 mRNA in these mice. The absence of IL-17 does not alter expression of the antimycobacterial genes, NO synthase 2 and LRG-47, and the absence of IL-23 or IL-17, both of which are implicated in mediating inflammation, fails to substantially affect the granulomatous response to M. tuberculosis infection of the lung. Despite this redundancy, IL-23 is required to provide a moderate level of protection in the absence of IL-12p70, and this protection correlates with a requirement for IL-23 in the IL-12p70-independent induction of Ag-specific, IFN-γ-producing CD4 T cells. We also show that IL-23 is required for the induction of an IL-17-producing Ag-specific phenotype in naive CD4 T cells in vitro and that absence of IL-12p70 promotes an increase in the number of IL-17-producing Ag-specific CD4 T cells both in vitro and in vivo.

“…Interestingly, IL-23p19 Ϫ/Ϫ mice infected with T. gondii did not show an altered resistance after infection (22). This may be related to the different nature of T. gondii vs C. neoformans infection and, in addition, only acute stages of infection were investigated in this study (22). Our studies of C. neoformans infection examine both early and late time points.…”

Section: Discussionmentioning

confidence: 99%

IL-23 Enhances the Inflammatory Cell Response in Cryptococcus neoformans Infection and Induces a Cytokine Pattern Distinct from IL-12

Kleinschek

Müller

Brodie³

et al. 2006

Self Cite

206

144

IL-23, a heterodimeric cytokine composed of the p40 subunit of IL-12 and a novel p19 subunit, has been shown to be a key player in models of autoimmune chronic inflammation. To investigate the role of IL-23 in host resistance during chronic fungal infection, wild-type, IL-12- (IL-12p35−/−), IL-23- (IL-23p19−/−), and IL-12/IL-23- (p40-deficient) deficient mice on a C57BL/6 background were infected with Cryptococcus neoformans. Following infection, p40-deficient mice demonstrated higher mortality than IL-12p35−/− mice. Reconstitution of p40-deficient mice with rIL-23 prolonged their survival to levels similar to IL-12p35−/− mice. IL-23p19−/− mice showed a moderately reduced survival time and delayed fungal clearance in the liver. Although IFN-γ production was similar in wild-type and IL-23p19−/− mice, production of IL-17 was strongly impaired in the latter. IL-23p19−/− mice produced fewer hepatic granulomata relative to organ burden and showed defective recruitment of mononuclear cells to the brain. Moreover, activation of microglia cells and expression of IL-1β, IL-6, and MCP-1 in the brain was impaired. These results show that IL-23 complements the more dominant role of IL-12 in protection against a chronic fungal infection by an enhanced inflammatory cell response and distinct cytokine regulation.