IFN-γ-mediated downregulation of LXA4 is necessary for the maintenance of nonresolving inflammation and papilloma persistence.

Abstract

Nonresolving inflammation is a hallmark of many types of tumors and the molecular mechanisms maintaining this inflammation are still largely unknown. In a two-stage carcinogenesis model, we observed here that the lack of IFN-γ receptor or neutralization of IFN-γ accelerated spontaneous papilloma regression in mice. The impaired maintenance of local inflammation was associated with reduced IFN-γ and enhanced biosynthesis of proresolution lipid mediator lipoxin A4 (LXA4). Interestingly, blocking LXA4 eliminated the effect of anti-IFN-γ, whereas treatment of mice with a therapeutic dose of LXA4 accelerated papilloma regression in an IFN-γ-independent manner. These results link for the first time a cytokine-dependent maintenance of inflammation with a downregulated production of proresolution lipid mediators. Strategies promoting spontaneous resolution of chronic inflammation by blocking IFN-γ and/or increasing LXA4 may be useful for the treatment of inflammation-associated tumors.