MAP3K8 Regulates Cox-2–Mediated Prostaglandin E2 Production in the Lung and Suppresses Pulmonary Inflammation and Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by exuberant deposition of extracellular matrix components, leading to the deterioration of lung architecture and respiratory functions. Profibrotic mechanisms are controlled by multiple regulatory molecules, including MAPKs, in turn regulated by multiple phosphorylation cascades. MAP3K8 is an MAPK kinase kinase suggested to pleiotropically regulate multiple pathogenic pathways in the context of inflammation and cancer; however, a possible role in the pathogenesis of IPF has not been investigated. In this report, <i>MAP3K8</i> mRNA levels were found decreased in the lungs of IPF patients and of mice upon bleomycin-induced pulmonary fibrosis. Ubiquitous genetic deletion of <i>Map3k8</i> in mice exacerbated the modeled disease, whereas bone marrow transfer experiments indicated that although MAP3K8 regulatory functions are active in both hematopoietic and nonhematopoietic cells, Map3k8 in hematopoietic cells has a more dominant role. Macrophage-specific deletion of <i>Map3k8</i> was further found to be sufficient for disease exacerbation thus confirming a major role for macrophages in pulmonary fibrotic responses and suggesting a main role for Map3k8 in the homeostasis of their effector functions in the lung. <i>Map3k8</i> deficiency was further shown to be associated with decreased <i>Cox-2</i> expression, followed by a decrease in PGE₂ production in the lung; accordingly, exogenous administration of PGE₂ reduced inflammation and reversed the exacerbated fibrotic profile of <i>Map3k8</i> ^-/- mice. Therefore, MAP3K8 has a central role in the regulation of inflammatory responses and Cox-2-mediated PGE₂ production in the lung, and the attenuation of its expression is integral to pulmonary fibrosis development.