TNF and IL-6 mediate MIP-1alpha expression in bleomycin-induced lung injury.
Previously, macrophage inflammatory protein-1alpha (MIP-1alpha), 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-1alpha protein with anti-MIP-1alpha antibodies significantly attenuated both mononuclear phagocyte recruitment and pulmonary fibrosis in bleomycin-challenged CBA/J mice. However, the specific stimuli for MIP-1alpha 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-1alpha 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-1alpha protein expression. Treatment of bleomycin-challenged mice with soluble TNF receptor (sTNFr) or anti-IL-6 antibodies significantly decreased MIP-1alpha protein expression in the lungs. Furthermore, normal alveolar macrophages secreted elevated levels of MIP-1alpha 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-1alpha 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-1alpha protein expression in the profibrotic inflammatory lesion during the response to intratracheal bleomycin challenge.
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
R E
RE
Smith
R M
RM
Strieter
S H
SH
Phan
N
N
Lukacs
S L
SL
Kunkel
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D007167:Immunotherapy; D017403:In Situ Hybridization; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008808:Mice, Inbred CBA; D008954:Models, Biological; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000502:physiology* / Q000627:therapeutic use; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*
D000906:Antibodies; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin