035. THE ROLE OF THE SERTOLI CELL IN REGULATING SPERMATOGENESIS, IMMUNE RESPONSES AND INFLAMMATORY DISEASE: MULTIPLE FUNCTIONS, COMMON MECHANISMS?

There is increasing evidence that the Sertoli cell, in addition to modulating responses to direct antigenic challenges (eg. intratesticular allografts), is central to the response of the testis to inflammation and infection. Systemic inflammation exerts an inhibitory effect on spermatogenesis, which has been attributed to the effects of fever, vascular disturbances, or loss of androgenic support. However, recent studies point to more direct effects of inflammation on spermatogenesis. The discovery that Sertoli cells express Toll-like receptors (TLR), and react to TLR ligands by producing inflammatory cytokines and other mediators, provides a mechanism to account for this direct inhibition. Moreover, the pattern of cytokines produced by the Sertoli cell during inflammation is highly characteristic. For example, when stimulated with TLR ligands the Sertoli cell produces the pro-inflammatory cytokines, interleukin-1α (IL1α) and IL6, and the regulatory cytokine, activin A, but does not produce IL1β and tumour necrosis factor-α, which are major pro-inflammatory products of activated macrophages. The disruptive effects of inflammation on spermatogenesis may be attributed to the elevated production of these cytokines, all of which have stimulatory or inhibitory effects on germ cell mitosis, meiosis and apoptosis and Sertoli cell tight junction formation, In addition, activation of TLR/IL1 mediated inflammatory pathways in the Sertoli cell inhibits its ability to respond to its principal trophic hormone, follicle-stimulating hormone. Studies on the regulation of these interactions will further establish the role of the Sertoli cell in inflammation and infection. However, such studies also have important implications for normal Sertoli cell function, as TLRs can respond to endogenous ligands as well. Consequently, the Sertoli cell may be viewed as a sentinel cell, supporting and protecting spermatogenesis when conditions are optimal, but rapidly shutting down spermatogenesis in the presence of infection or illness. Intriguingly, these apparently disparate roles appear to involve common inflammation-related mechanisms.