Interleukins 17 and 23 Influence the Host Response to Histoplasma capsulatum

Host defenses against Histoplasma capsulatum require the action of several cytokines. Here, we explored the influence of interleukin (IL)-17 and IL-23 on immunity to H. capsulatum infection in mice. In lungs, synthesis of IL-17 was up-regulated during acute infection, and the cells producing it were predominantly CD3(+). Neutralization of IL-17A blunted fungal clearance but did not promote progressive infection. Decreased inflammatory cell recruitment and increased levels of IL-6 and IL-10 were associated with impaired clearance. To determine whether the elevated cytokine levels were important in the action of IL-17A, IL-6(-/-) or IL-10(-/-) mice were treated with anti-IL-17A; neutralization of IL-17A did not alter fungal burden in either group of knockout mice. We explored the relationship between IL-17 and IL-23 because they have been reported to form a regulatory network. IL-23 transcription and protein level were increased in the lungs of infected mice. Mice producing IL-23 in the absence of IL-12 manifested prolonged survival that was IL-17 dependent. Thus, IL-17 is requisite for the generation of optimal inflammatory and protective responses. Generation of functional IL-17(+) cells is dependent on IL-6 and IL-10. Our findings also establish the existence a regulatory IL-17/IL-23 axis in histoplasmosis.