TNF and IL‐6 mediate MIP‐1α expression in bleomycin‐induced lung injury

Abstract

Previously, macrophage inflammatory protein‐1α (MIP‐1α), a member of the C‐C chemokine family, has been implicated in bleomycin‐induced pulmonary fibrosis, a model of the human disease idiopathic pulmonary fibrosis. Neutralization of MIP‐1α protein with anti‐MIP‐1α antibodies significantly attenuated both mononuclear phagocyte recruitment and pulmonary fibrosis in bleomycin‐challenged CBA/J mice. However, the specific stimuli for MIP‐1α expression in the bleomycin‐induced lesion have not been characterized. In this report, two mediators of the inflammatory response to bleomycin, tumor necrosis factor (TNF) and interleukin‐6 (IL‐6), were evaluated as putative stimuli for MIP‐1α expression after bleomycin challenge in CBA/J mice. Elevated levels of bioactive TNF and IL‐6 were detected in bronchoalveolar lavage (BAL) fluid and lung homogenates from bleomycin‐treated CBA/J mice at time points post‐bleomycin challenge, which precede MIP‐1α protein expression. Treatment of bleomycin‐challenged mice with soluble TNF receptor (sTNFr) or anti‐IL‐6 antibodies significantly decreased MIP‐1α protein expression in the lungs. Furthermore, normal alveolar macrophages secreted elevated levels of MIP‐1α protein in 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‐1α protein, compared to controls, when treated with TNF alone. Based on the data presented here, we propose that TNF and IL‐6 are part of a cytokine network that modulates MIP‐1α protein expression in the profibrotic inflammatory lesion during the response to intratracheal bleomycin challenge. J. Leukoc. Biol. 64: 528–536; 1998.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141711/1/jlb0528.pd