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Lung fibroblasts produce interleukin-33 in response to stimulation by retinoblastoma-binding protein 9 via production of prostaglandin E2.

Takumi Adachi,K. Yasuda,T. Muto,S. Serada,T. Yoshimoto,K. Ishii,E. Kuroda,K. Araki,M. Ohmuraya,T. Naka,K. Nakanishi

Published 2020 in International Immunology

ABSTRACT

Intestinal nematode infection induces pulmonary eosinophilia via interleukin (IL)-33, although the mechanism of pulmonary IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intranasal administration of a lung extract induced IL-33 production in lungs. Additionally, lung extracts increased Il33 mRNA expression in primary lung fibroblasts. Proteomic analysis identified retinoblastoma-binding protein 9 (RBBP9) as a major DAMPs with IL33ia. RBBP9 was originally discovered as a protein that provides cells with resistance to the growth inhibitory effect of transforming growth factor (TGF)-β1. Here, we found that stimulation by RBBP9 induced primary fibroblasts to produce prostaglandin E2 (PGE2) that, in turn, induced fibroblasts to produce IL-33. RBBP9-activated fibroblasts expressed mRNAs of cyclooxygenase-2 (COX-2) and PGE2 synthase-1 that convert arachidonic acid to PGE2. Furthermore, they expressed PGE2 receptors E-prostanoid (EP) 2 and EP4. Thus, treatment with a COX-2 inhibitor or EP2 and/or EP4 receptor antagonists inhibited RBBP9-induced IL-33 production. Nematode infection induced pulmonary Il33 mRNA expression, which was inhibited by the COX-2 inhibitor or EP2 and EP4 antagonists, suggesting that nematode infection induced pulmonary Il33 mRNA via PGE2. RBBP9 was expressed constitutively in the lung in a steady state, which did not increase after nematode infection. Finally, we found that Rbbp9-deficient mice had a significantly diminished capacity to increase pulmonary Il33 mRNA expression following nematode infection. Thus, the PGE2-EP2/EP4 pathway activated by RBBP9 released from damaged lungs is important for pulmonary IL-33 production in nematode-infected animals.

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