Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5G 1L5, Ontario, Canada.
Biol Chem. 2010 Jan;391(1):85-95. doi: 10.1515/BC.2010.007.
Transforming growth factor beta1 (TGF beta 1) has been implicated as a key contributor of immunosuppression in seminal plasma. The biochemical mechanisms that lead to production of active seminal TGF beta 1 are not fully understood. It is plausible that TGF beta 1 activation is partly induced simultaneously with the release of motile spermatozoa following liquefaction of the semen coagulum. Several members of the kallikrein-related peptidase (KLK) family are involved in the regulation of semen liquefaction. This study examines the involvement of these KLKs in TGF beta 1 activation in vitro and ex vivo, in seminal plasma. Latent TGF beta 1 was rapidly activated by KLK14. The latency-associated propeptide (LAP) was shown to be cleaved by KLK14 into small peptide fragments, providing a possible mechanism for TGF beta 1 activation. KLK14 also cleaved the latent TGFbeta binding protein 1 (LTBP1). KLK1, 2, and 5 might also contribute to TGF beta 1 activation by nicking the LAP motif and inducing conformational changes that aid in subsequent processing of LAP or through LTBP1 cleavage. Our study provides strong evidence for the involvement of multiple members of the seminal KLK cascade in activation of latent TGF beta 1 in seminal plasma. These findings might have clinical implications in infertility treatment of cases with concurrent delayed liquefaction and TGF beta 1-related semen antigenicity.
转化生长因子-β1（TGF-β1）被认为是精液中免疫抑制的关键因素。导致活性精液 TGF-β1 产生的生化机制尚未完全阐明。TGF-β1 的激活可能部分是在精液凝块液化后精子游动的同时被诱导的。激肽释放酶相关肽酶（KLK）家族的几个成员参与了精液液化的调节。本研究探讨了这些 KLK 在体外和体内精液中 TGF-β1 激活中的作用。潜伏 TGF-β1 被 KLK14 迅速激活。Latency-associated propeptide（LAP）被证明被 KLK14 切割成小肽片段，为 TGF-β1 激活提供了一种可能的机制。KLK14 还切割潜伏 TGFβ 结合蛋白 1（LTBP1）。KLK1、2 和 5 也可能通过切割 LAP 基序和诱导构象变化来促进 LAP 的后续加工或通过 LTBP1 切割来促进 TGF-β1 的激活。我们的研究为精液 KLK 级联中的多个成员参与激活潜伏 TGF-β1 提供了有力证据在精液中。这些发现可能对同时存在液化延迟和 TGF-β1 相关精液抗原性的不育症治疗具有临床意义。
