TNF AND IL-6 MEDIATE MIP-1-ALPHA EXPRESSION IN BLEOMYCIN-INDUCED LUNGINJURY

Previously, macrophage inflammatory protein-1 alpha (MIP-1 alpha), a m ember of the C-C chemokine family, has been implicated in bleomycin-in duced pulmonary fibrosis, a model of the human disease idiopathic pulm onary fibrosis, Neutralization of MIP-1 alpha protein with anti-MIP-1 alpha antibodies significantly attenuated both mononuclear phagocyte r ecruitment and pulmonary fibrosis in bleomycin-challenged CBA/J mice, However, the specific stimuli for MIP-1 alpha expression in the bleomy cin-induced lesion have not been characterized. In this report, two me diators of the inflammatory response to bleomycin, tumor necrosis fact or (TNF) and interleukin-6 (IL-6), were evaluated as putative stimuli for MIP-1 alpha expression after bleomycin challenge in CBA/J mice. El evated levels of bioactive TNF and IL-6 were detected in bronchoalveol ar lavage (BAL) fluid and lung homogenates from bleomycin-treated CBA/ J mice at time points post-bleomycin challenge, which precede MIP-1 al pha protein expression. Treatment of bleomycin-challenged mice with so luble TNF receptor (sTNFr) or anti-IL-6 antibodies significantly decre ased MIP-1 alpha protein expression in the lungs. Furthermore, normal alveolar macrophages secreted elevated levels of MIP-1 alpha protein i n response to treatment with TNF plus IL-6 or bleomycin plus IL-6, but not TNF, bleomycin, or IL-6 alone. Finally, leukocytes recovered from the BAL fluid of bleomycin-challenged mice secreted higher levels of MIP-1 alpha protein, compared to controls, when treated with TNF alone . Based on time data presented here, we propose that TNF and IL-6 are part of a cytokine network that modulates MIP-1 alpha protein expressi on in the profibrotic inflammatory lesion during the response to intra tracheal bleomycin challenge.