Abstract

Recruited eosinophils in pulmonary fibrosis can play a role in tissue remodeling but its role is not fully understood. A novel secreted protein, found in inflammatory zone 1 (FIZZ1) is highly induced in bleomycin-induced lung injury. It is primarily localized to lung epithelial cells and mononuclear phagocytes. It has potential fibrogenic properties due to its ability to induce myofibroblast differentiation and enhance fibroblast resistance to apoptosis. In this study, the ability of eosinophils to regulate epithelial FIZZ1 expression was analyzed. Eosinophil and alveolar epithelial type II cell (AEC) co-cultures induced AEC FIZZ1 expression, which was significantly suppressed only by antibodies to IL-16. Cytokine array analysis confirmed that eosinophils from fibrotic lung expressed IL-16. Moreover IL-16 stimulated AEC FIZZ1 expression in a dose dependent manner, and AECs were found to express CD9, a putative IL-16 receptor. Suppression of CD9 expression by CD9 siRNA significantly inhibited AEC FIZZ1 expression by 67%. However antibodies to CD9 stimulated FIZZ1 expression indicating perhaps that antibody binding could activate CD9 signaling. These findings suggest that eosinophil-derived IL16 is capable of regulating FIZZ1 expression in AECs via binding to CD9. This may represent another pathway by which eosinophils could promote tissue fibrosis.

Supported by NIH grants HL28737, HL31963, HL 52285 and HL77297

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