Potential role of multiple members of the kallikrein-related peptidase family of serine proteases in activating latent TGFβ1 in semen

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.