Fjellbirkeland Lars, Cambier Stephanie, Broaddus V Courtney, Hill Arthur, Brunetta Paul, Dolganov Gregory, Jablons David, Nishimura Stephen L
Department of Anatomic Pathology and Lung Biology Center, San Francisco General Hospital, University of California at San Francisco/Mt. Zion Cancer Center, San Francisco, California 94110, USA.
Am J Pathol. 2003 Aug;163(2):533-42. doi: 10.1016/s0002-9440(10)63681-4.
Transforming growth factor (TGF)-beta is a potent multifunctional cytokine that is an essential regulator of epithelial proliferation. Because TGF-beta is expressed almost entirely in a latent state in vivo, a major source of regulation of TGF-beta function is its activation. A subset of integrins, alphavbeta8 and alphavbeta6, which are expressed in the human airway, has recently been shown to activate latent TGF-beta in vitro, suggesting a regulatory role for integrins in TGF-beta function in vivo. Here we have developed a novel, biologically relevant experimental model of human airway epithelium using intact human bronchial tissue. We have used this model to determine the function of integrin-mediated activation of TGF-beta in the airway. In human bronchial fragments cultured in vitro, authentic epithelial-stromal interactions were maintained and integrin and TGF-beta expression profiles correlated with profiles found in normal lung. In addition, in this model, we found that either the integrin alphavbeta8 or TGF-beta could inhibit airway epithelial cell proliferation. Furthermore, we found that one mechanism of integrin-alphavbeta8-dependent inhibition of cell proliferation was through activation of TGF-beta because anti-beta8 antibody blocked the majority (76%) of active TGF-beta released from bronchial fragments. These data provide compelling evidence for a functional role for integrin-mediated activation of TGF-beta in control of human airway epithelial proliferation in vivo.
转化生长因子（TGF）-β是一种强大的多功能细胞因子，是上皮细胞增殖的重要调节因子。由于TGF-β在体内几乎完全以潜伏状态表达，TGF-β功能调节的一个主要来源是其激活。整合素的一个亚群，αvβ8和αvβ6，在人类气道中表达，最近已被证明在体外可激活潜伏的TGF-β，这表明整合素在体内TGF-β功能中具有调节作用。在这里，我们使用完整的人支气管组织开发了一种新型的、与生物学相关的人气道上皮实验模型。我们使用这个模型来确定整合素介导的TGF-β在气道中的激活功能。在体外培养的人支气管片段中，维持了真实的上皮-基质相互作用，整合素和TGF-β的表达谱与正常肺中的谱相关。此外，在这个模型中，我们发现整合素αvβ8或TGF-β都可以抑制气道上皮细胞增殖。此外，我们发现整合素αvβ8依赖性抑制细胞增殖的一种机制是通过激活TGF-β，因为抗β8抗体阻断了从支气管片段释放的大部分（76%）活性TGF-β。这些数据为整合素介导的TGF-β激活在体内控制人气道上皮增殖中的功能作用提供了令人信服的证据。
