IFNγ-mediated exacerbation of Saccharopolyspora rectivirgula-induced proinflammatory responses is dependent on interferon regulatory factor 1 (INM3P.403)

Abstract

Abstract Saccharopolyspora rectivirgula (SR) is a thermophilic actinomycetes that causes hypersensitivity pneumonitis (HP). Interferon γ (IFNγ) produced after exposure to SR has been demonstrated to be necessary for development of HP. However, the molecular mechanism by which IFNγ enhances SR-mediated inflammatory responses is not completely understood. We investigated how IFNγ alters SR-induced expression of cytokines/chemokines. IFNγ pretreatment substantially enhanced expression of TNFα, IL-6, IL-23, IFNβ, MIP-1α, and MIP-2, without affecting IL-10 expression, in response to SR. Expression of interferon regulatory factor 1 (IRF1) was rapidly increased in cells pre-exposed to IFNγ, and inhibition of IRF1 synthesis abolished IFNγ-enhanced gene expression in response to SR. In contrast, suppression of IRF1 expression did not alter SR-mediated expression of IL-10. SR stimulation led to the binding of IRF1 to the IL-6 promoter region, but not to the IL-10 promoter region in IFNγ-pretreated cells. This indicates that IRF1 expressed in cells pre-exposed to IFNγ is activated by subsequent SR stimulation and contributes to the synergistic expression of certain proinflammatory genes. Our results imply that IFNγ produced after initial exposure to SR may help direct the proinflammatory responses to subsequent SR exposure toward to pathogenic Th1/Th17 development by selectively amplifying expression of certain cytokines/chemokines without affecting expression of regulatory cytokine IL-10.