Lee Kuy-Sook, Park Jin-Hee, Lee Seahyoung, Lim Hyun-Joung, Choi Hye-Eun, Park Hyun-Young
Center for Biomedical Sciences, Division of Cardiovascular Diseases, National Institute of Health, Seoul, Korea.
Biochim Biophys Acta. 2007 Nov;1773(11):1637-44. doi: 10.1016/j.bbamcr.2007.07.001. Epub 2007 Jul 17.
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family that binds to and activates EGF receptor, and is expressed in a variety of tissues, predominantly in the lung, heart, brain and skeletal muscle. HB-EGF is known to induce vascular smooth muscle cell (VSMC) proliferation by activating PI3K-Akt and MAPK pathway. However, our preliminary data showed that Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway was also involved in HB-EGF induced VSMC proliferation. More interestingly, HB-EGF (10 ng/ml) induced a biphasic activation of STAT3 (early at 5 min and late at 60-120 min). Therefore, we tried to elucidate the underlying mechanism of this delayed STAT3 activation by HB-EGF in VSMCs. First, we examined the effect of HB-EGF on interleukin-6 (IL-6) mRNA expressions, since IL-6 have been implicated in the regulation of STAT3 activation. According to our data, HB-EGF increased transcription of IL-6, cardiotrophin-1 (CT-1), leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). The secretion of IL-6 was also increased by HB-EGF. Furthermore, these HB-EGF-mediated up-regulation of IL-6 mRNA expression and secretion were inhibited by NF-kappaB inhibitor Bay117082 (2.5 microM) treatment suggesting involvement of NF-kappaB pathway. Again, the late activation of STAT3 by HB-EGF was abolished by both Bay117082 and IL-6 neutralizing antibody (1 microg/ml) indicating IL-6 is a key molecule in the delayed activation of STAT3 by HB-EGF. In addition, IL-6 neutralizing antibody inhibited both HB-EGF conditioned media induced STAT3 activation and HB-EGF induced VSMC proliferation. In conclusion, IL-6 plays an important role in the delayed activation of STAT3 and VSMC proliferation induced by HB-EGF.
肝素结合表皮生长因子样生长因子（HB-EGF）是表皮生长因子（EGF）家族的成员，它能与EGF受体结合并激活该受体，在多种组织中表达，主要存在于肺、心脏、大脑和骨骼肌中。已知HB-EGF可通过激活PI3K-Akt和MAPK途径诱导血管平滑肌细胞（VSMC）增殖。然而，我们的初步数据表明，Janus激酶-信号转导子和转录激活子（JAK-STAT）途径也参与了HB-EGF诱导的VSMC增殖。更有趣的是，HB-EGF（10 ng/ml）诱导了STAT3的双相激活（早期在5分钟，晚期在60-120分钟）。因此，我们试图阐明HB-EGF在VSMC中延迟激活STAT3的潜在机制。首先，我们检测了HB-EGF对白细胞介素-6（IL-6）mRNA表达的影响，因为IL-6与STAT3激活的调节有关。根据我们的数据，HB-EGF增加了IL-6、心肌营养素-1（CT-1）、白血病抑制因子（LIF）和睫状神经营养因子（CNTF）的转录。HB-EGF也增加了IL-6的分泌。此外，NF-κB抑制剂Bay117082（2.5 microM）处理可抑制这些HB-EGF介导的IL-6 mRNA表达和分泌的上调，提示NF-κB途径的参与。同样，Bay117082和IL-6中和抗体（1 microg/ml）均可消除HB-EGF对STAT3的晚期激活，表明IL-6是HB-EGF延迟激活STAT3的关键分子。此外，IL-6中和抗体抑制了HB-EGF条件培养基诱导的STAT3激活和HB-EGF诱导的VSMC增殖。总之，IL-6在HB-EGF诱导的STAT3延迟激活和VSMC增殖中起重要作用。
