TNF and IL-6 mediate MIP-1a expression in bleomycin-induced lung injury

Abstract: Previously, macrophage inflammatory protein-1a (MIP-1a), a member of the C-C chemo-kine family, has been implicated in bleomycin-induced pulmonary fibrosis, a model of the human disease idiopathic pulmonary fibrosis. Neutraliza-tion of MIP-1a protein with anti-MIP-1a antibodies significantly attenuated both mononuclear phago-cyte recruitment and pulmonary fibrosis in bleomy-cin-challenged CBA/J mice. However, the specific stimuli for MIP-1a expression in the bleomycin-induced lesion have not been characterized. In this report, two mediators of the inflammatory re-sponse to bleomycin, tumor necrosis factor (TNF) and interleukin-6 (IL-6), were evaluated as putative stimuli for MIP-1a expression after bleomycin challenge in CBA/J mice. Elevated levels of bioac-tive TNF and IL-6 were detected in bronchoalveo-lar lavage (BAL) fluid and lung homogenates from bleomycin-treated CBA/J mice at time points post-bleomycin challenge, which precede MIP-1a pro-tein expression. Treatment of bleomycin-chal-lenged mice with soluble TNF receptor (sTNFr) or anti-IL-6 antibodies significantly decreased MIP-1a protein expression in the lungs. Furthermore, nor-mal alveolar macrophages secreted elevated levels of MIP-1a protein in response to treatment wit