Abstract
Changes in the wall of seminiferous tubules in men with impaired spermatogenesis imply sterile inflammation of the testis. We tested the hypothesis that the cells forming the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), orchestrate inflammatory events and that Toll like receptors (TLRs) and danger signals from the extracellular matrix (ECM) of this wall are involved. In cultured HTPCs we detected TLRs, including TLR2. A TLR-2 ligand (PAM) augmented interleukin 6 (IL-6), monocyte chemo-attractant protein-1 (MCP-1) and pentraxin 3 (PTX3) in HTPCs. The ECM-derived proteoglycan biglycan (BGN) is secreted by HTPCs and may be a TLR2-ligand at HTPCs. In support, recombinant human BGN increased PTX3, MCP-1 and IL-6 in HTPCs. Variable endogenous BGN levels in HTPCs derived from different men and differences in BGN levels in the tubular wall in infertile men were observed. In testes of a systemic mouse model for male infertility, testicular sterile inflammation and elevated estradiol (E2) levels, BGN was also elevated. Hence we studied the role of E2 in HTPCs and observed that E2 elevated the levels of BGN. The anti-estrogen ICI 182,780 blocked this action. We conclude that TLR2 and BGN contribute to sterile inflammation and infertility in man.
Highlights
Recent studies of isolated human TPCs (HTPCs) revealed that they secrete a plethora of factors, including components of the ECM, growth factors and immunological factors[12,13]
TLR2 protein was identified in human testicular sections in typical peritubular cells, as well as in cells of the tubular and interstitial compartments (Fig. 1B)
PAM (Pam3Cys-Ser-(Lys)4), a ligand for TLR2/122,23, evoked strong responses in HTPCs. It augmented the production of PTX3 (Western blotting) and the secretion of IL-6 and MCP-1 (ELISA; Fig. 2). This indicates that the TLR2 is functional in HTPCs
Summary
Recent studies of isolated human TPCs (HTPCs) revealed that they secrete a plethora of factors, including components of the ECM, growth factors and immunological factors[12,13]. In addition a series of studies provide compelling evidence that it can act as a ligand at Toll like receptors (TLRs), namely TLR2/4, expressed by macrophages. BGN may be an ECM-derived factor able to foster inflammation[18,19,20,21]. Whether HTPCs express TLRs, in particular TLR2, and whether BGN serves as a ligand and may be able to influence HTPCs is not known. We studied the expression of TLRs and BGN, examined aspects of BGN regulation and the possibility that it can function as a signal molecule from the ECM to foster inflammation in human testes. We employed HTPCs as a cellular model and studied testicular samples of infertility patients and AROM+mice
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