Gunella Gabriele, Bardelli Claudio, Amoruso Angela, Viano Ilario, Balbo Piero, Brunelleschi Sandra
Department of Medical Sciences, School of Medicine, University of Piemonte Orientale A. Avogadro, Novara, Italy.
Br J Pharmacol. 2006 Jun;148(4):478-89. doi: 10.1038/sj.bjp.0706751. Epub 2006 Apr 24.
Macrophage activation is a key feature of inflammatory reactions occurring during bacterial infections, immune responses and tissue injury. We previously demonstrated that human macrophages of different origin express the tyrosine kinase receptor recepteur d'origine nantaise, the human receptor for MSP (RON) and produce superoxide anion (O(2)(-)) when challenged with macrophage-stimulating protein (MSP), the endogenous ligand for RON. This study was aimed to evaluate the role of MSP in alveolar macrophages (AM) isolated from healthy volunteers and patients with interstitial lung diseases (sarcoidosis, idiopathic pulmonary fibrosis), either smokers or non-smokers, by evaluating the respiratory burst, cytokine release and nuclear factor-kappa B (NF-kappaB) activation. MSP effects were compared with those induced by known AM stimuli, for example, phorbol myristate acetate, N-formyl-methionyl-leucyl-phenylalanine, lipopolysaccharide.MSP evokes O(2)(-) production, cytokine release and NF-kappaB activation in a concentration-dependent manner. By evaluating the respiratory burst, we demonstrate a significantly increased O(2)(-) production in AM from healthy smokers or smokers with pulmonary fibrosis, as compared to non-smokers, thus suggesting MSP as an enhancer of cigarette smoke toxicity. Besides inducing interleukin-1 beta (IL-1beta) and interleukin-10 (IL-10) production, MSP triggers an enhanced tumor necrosis factor-alpha release, especially in healthy and pulmonary fibrosis smokers. On the contrary, MSP-induced IL-10 release is higher in AM from healthy non-smokers. MSP activates the transcription factor NF-kappaB; this effect is more potent in healthy and fibrosis smokers (2.5-fold increase in p50 subunit translocation). This effect is receptor-mediated, as it is prevented by a monoclonal anti-human MSP antibody. The higher effectiveness of MSP in AM from healthy smokers and patients with pulmonary fibrosis is suggestive of its role in these clinical conditions.
巨噬细胞活化是细菌感染、免疫反应和组织损伤期间发生的炎症反应的关键特征。我们之前证明，不同来源的人类巨噬细胞表达酪氨酸激酶受体南特起源受体（RON），即MSP的人类受体，并且在用巨噬细胞刺激蛋白（MSP）（RON的内源性配体）刺激时会产生超氧阴离子（O₂⁻）。本研究旨在通过评估呼吸爆发、细胞因子释放和核因子-κB（NF-κB）活化，来评价MSP在从健康志愿者以及间质性肺疾病（结节病、特发性肺纤维化）患者（吸烟者或非吸烟者）分离出的肺泡巨噬细胞（AM）中的作用。将MSP的作用与已知的AM刺激物（例如佛波酯、N-甲酰甲硫氨酰亮氨酰苯丙氨酸、脂多糖）诱导的作用进行比较。MSP以浓度依赖性方式引发O₂⁻产生、细胞因子释放和NF-κB活化。通过评估呼吸爆发，我们证明，与非吸烟者相比，健康吸烟者或患有肺纤维化的吸烟者的AM中O₂⁻产生显著增加，因此提示MSP是香烟烟雾毒性的增强剂。除了诱导白细胞介素-1β（IL-1β）和白细胞介素-10（IL-10）产生外，MSP还引发肿瘤坏死因子-α释放增加，尤其是在健康和患有肺纤维化的吸烟者中。相反，MSP诱导的IL-10释放在健康非吸烟者的AM中更高。MSP激活转录因子NF-κB；这种作用在健康和患有纤维化的吸烟者中更强（p50亚基易位增加2.5倍）。这种作用是受体介导的，因为它可被单克隆抗人MSP抗体阻断。MSP在健康吸烟者和肺纤维化患者的AM中具有更高的效力，提示了其在这些临床病症中的作用。
