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Transforming Growth Factor ß3 Regulates the Dynamics of Sertoli Cell Tight Junctions Via the p38 Mitogen-Activated Protein Kinase Pathway¹

Population Council, Center for Biomedical Research,³ New York, New York 10021 Department of Zoology,⁴ The University of Hong Kong, Hong Kong, Special Administrative Region of China

Earlier studies have implicated the significance of transforming growth factor-ß3 (TGFß3) in the regulation of Sertoli cell tight junction (TJ) dynamics, possibly via its inhibitory effects on the expression of occludin, claudin-11, and zonula occludens-1 (ZO-1). Yet the mechanism by which TGFß3 regulates the Sertoli cell TJ-permeability barrier is not known. Using techniques of semiquantitative reverse transcription-PCR (RT-PCR), immunoblotting, immunohistochemistry, and inhibitors against different kinases coupled with physiological techniques to assess the Sertoli cell TJ barrier function, it was shown that this TGFß3-induced effect on Sertoli cell TJ dynamics is mediated via the p38 mitogen-activated protein (MAP) kinase pathway. First, the assembly of the Sertoli cell-TJ barrier was shown to be associated with a transient but significant decline in both the TGFß3 production and expression by Sertoli cells. Furthermore, addition of TGFß3 to Sertoli cell cultures during TJ assembly indeed perturbed the TJ barrier with an IC₅₀ at 9 pM. Second, the TGFß3-induced disruption of the TJ barrier was associated with a transient induction in MEKK2 but not the other upstream signaling molecules that mediate TGFß3 action, such as Smad2, Cdc42, Rac2, and N-Ras, suggesting this effect might be mediated via the p38 MAP kinase pathway. This postulate was confirmed by the observation that TGFß3 also induced the protein level of the activated and phosphorylated form of p38 MAP kinase at the time the TJ barrier was perturbed. Third, and perhaps the most important of all, this TGFß3-mediated inhibitory effect on the TJ barrier and the TGFß3-induced p-p38 MAP kinase production could be blocked by SB202190, a specific p38 MAP kinase inhibitor, but not U0126, a specific MEK1/2 kinase inhibitor. These results thus unequivocally demonstrate that TGFß3 utilizes the p38 MAP kinase pathway to regulate Sertoli cell TJ dynamics.

¹ This work was supported in part by grants from the CONRAD Program (CICCR, CIG 96-05-A, and CIG 01-72 to C.Y.C.), the Noopolis Foundation (to C.Y.C.), the National Institutes of Heath (NICHD, U54-HD29990, Project 3, to C.Y.C.), the United States Agency for International Development (USAID, HRN-A-00-99-00010 Subproject: AF2364 toxicity study to C.Y.C.) and Hong Kong Research Grant Council (HKU 7194/01M to W.M.L. and C.Y.C.). W.Y.L. was supported in part by a Hong Kong University Research Scholarship Award.

² Correspondence: C. Yan Cheng, Population Council, 1230 York Avenue, New York, NY 10021. FAX: 212 327 8733; Y-Cheng{at}popcbr.rockefeller.edu

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