Cagnoni Francesca, Oddera Susanna, Giron-Michel Julien, Riccio Anna Maria, Olsson Susanna, Dellacasa Palmiro, Melioli Giovanni, Canonica G Walter, Azzarone Bruno
Allergy and Respiratory Disease Clinic, Department of Internal Medicine, University of Genoa, Genoa, Italy.
J Immunol. 2004 Mar 1;172(5):3205-14. doi: 10.4049/jimmunol.172.5.3205.
CD40/CD40 ligand interaction is an important pathway for B and T cell cooperation and function; functional CD40 molecules have recently been found on nonhematopoietic cells. We detected CD40 in vivo on normal human respiratory epithelial cells and showed that its expression is increased on inflamed airway epithelium. Subsequently, we analyzed its expression and function on primary cultures of human airway epithelial cells. Our data show that CD40 is up-regulated by IFN-beta and IFN-gamma, its ligation increases the surface expression of CD54 and CD106 and it may stimulate the release of IL-6 and IL-8. The use of Janus kinase 3 (JAK3) and NF-kappaB inhibitors suggests that both basal and CD40-induced release of the two cytokines is JAK3-dependent. Using colocalization techniques, we revealed the existence of CD40/JAK3 and CD40/TNFR-associated factor 2 interplay. The extent of these interactions may be partial (2-40% of the cells) or massive (80-90% of the cells) in cultured cells. Stimulation via CD40 causes a significant increase in the number of cells expressing colocalization only in the cultures displaying low frequency of initial colocalization. Thus, airway epithelial cells, activated by CD40, may behave as effector cells of the inflammation process and should be considered priority targets for anti-inflammatory therapy. This work identifies CD40 and the correlated JAK3 signaling molecule as potential molecular targets to block the inflammatory functions of epithelial cells.
CD40/CD40配体相互作用是B细胞与T细胞协作及发挥功能的重要途径；最近在非造血细胞上发现了功能性CD40分子。我们在体内检测到正常人呼吸道上皮细胞上存在CD40，并表明其在炎症气道上皮上的表达增加。随后，我们分析了其在人气道上皮细胞原代培养物中的表达及功能。我们的数据显示，CD40可被IFN-β和IFN-γ上调，其连接可增加CD54和CD106的表面表达，并且可能刺激IL-6和IL-8的释放。使用Janus激酶3（JAK3）和NF-κB抑制剂表明，这两种细胞因子的基础释放及CD40诱导的释放均依赖于JAK3。通过共定位技术，我们揭示了CD40/JAK3和CD40/TNFR相关因子2相互作用的存在。在培养细胞中，这些相互作用的程度可能是部分的（2%-40%的细胞）或大量的（80%-90%的细胞）。通过CD40刺激仅在初始共定位频率较低的培养物中导致表达共定位的细胞数量显著增加。因此，被CD40激活的气道上皮细胞可能作为炎症过程的效应细胞，应被视为抗炎治疗的优先靶点。这项工作确定CD40和相关的JAK3信号分子是阻断上皮细胞炎症功能的潜在分子靶点。
