Smith R E, Strieter R M, Phan S H, Lukacs N, Kunkel S L
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
J Leukoc Biol. 1998 Oct;64(4):528-36.
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.
此前，C-C趋化因子家族成员巨噬细胞炎性蛋白-1α（MIP-1α）已被证明与博来霉素诱导的肺纤维化有关，这是人类特发性肺纤维化疾病的一种模型。用抗MIP-1α抗体中和MIP-1α蛋白可显著减轻博来霉素攻击的CBA/J小鼠的单核吞噬细胞募集和肺纤维化。然而，博来霉素诱导损伤中MIP-1α表达的具体刺激因素尚未明确。在本报告中，评估了对博来霉素炎症反应的两种介质，肿瘤坏死因子（TNF）和白细胞介素-6（IL-6），作为CBA/J小鼠博来霉素攻击后MIP-1α表达的假定刺激因素。在博来霉素攻击后的时间点，在博来霉素处理的CBA/J小鼠的支气管肺泡灌洗（BAL）液和肺匀浆中检测到生物活性TNF和IL-6水平升高，这先于MIP-1α蛋白表达。用可溶性TNF受体（sTNFr）或抗IL-6抗体处理博来霉素攻击的小鼠可显著降低肺中MIP-1α蛋白表达。此外，正常肺泡巨噬细胞在接受TNF加IL-6或博来霉素加IL-6处理时分泌的MIP-1α蛋白水平升高，但单独使用TNF、博来霉素或IL-6时则不然。最后，与对照组相比，从博来霉素攻击小鼠的BAL液中回收的白细胞在用TNF单独处理时分泌的MIP-1α蛋白水平更高。基于此处提供的数据，我们提出TNF和IL-6是细胞因子网络的一部分，该网络在气管内博来霉素攻击反应期间调节纤维化炎症损伤中MIP-1α蛋白的表达。
