Regulatory Cytokine Expression and Interstitial Fluid Formation in the Normal and Inflamed Rat Testis Are Under Leydig Cell Control

Abstract

Leydig cells have been implicated in several inflammation-related responses of the testis. Specifically, these cells produce the proinflammatory cytokines interleukin-1 (IL-1) and IL-6, stimulate macrophage recruitment, and promote interstitial fluid formation. In addition, the immunoregulatory cytokines macrophage migration inhibitory factor (MIF), transforming growth factor-␤1 (TGF␤1), and interferon-␥ (IFN␥) are constitutively expressed by testicular cells, including the Leydig cells. In the present study, the contribution of the Leydig cell to testicular inflammatory responses was examined in adult male rats treated with the Leydig cell-specific toxin, ethane dimethane sulfonate (EDS). Intratesticular testosterone levels were modulated by subcutaneous testosterone implants. After 10 days, animals received an injection of lipopolysaccharide (LPS) to induce an inflammatory response, or saline alone, and were killed 3 hours later. Both depletion of Leydig cells by EDS and LPS treatment caused a decrease in collected testicular interstitial fluid to about 35% of control levels, but the effects were not additive. Maintenance of intratesticular testosterone reversed the interstitial fluid decline following EDS treatment and partially prevented the LPSinduced effect. MIF, TGF␤1, and IFN␥ were expressed in both the normal and inflamed testis at similar levels. In contrast, EDS treatment caused a significant decline in expression of all 3 cytokines, which was prevented by the testosterone implants. These data indicate that 1) expression of TGF␤1, MIF, and IFN␥ in the testis is not dependent on the presence of intact Leydig cells but is under direct testosterone control and 2) the decline in testicular interstitial fluid during inflammation involves the Leydig cells, acting via both androgens and nonandrogenic secretions. These data provide further support for a significant role for the Leydig cell in modulating the testicular response to inflammation.

Adrenomedullin protects Leydig cells against lipopolysaccharide-induced oxidative stress and inflammatory reaction via MAPK/NF-κB signalling pathways

“…LPS can induce the production of inflammatory factors, such as TNF-α and IL-1β, and subsequently suppress steroidogenesis by Leydig cells 39 . In an in vivo model of LPS injection to induce inflammatory response, the expression levels of TGF-β1 and MIF in the testis are not dependent on the presence of intact Leydig cells but are under direct testosterone control 40 . The ability of the Sendai virus to induce chemokine production in Leydig cells, such as MCP-1, may therefore increase leukocyte recruitment to the infection sites 41 .…”

Donor Sertoli cells transplanted into irradiated rat testes stimulate partial recovery of endogenous spermatogenesis

“…It is also possible that an increase in non-Leydig-cell interstitial cellularity and the de novo formed tubules in the interstitium segregate the testosterone-producing Leydig cells from the host seminiferous tubules, which also reduces local Same definitions of injection types and numbers of testes as in Table 1. testosterone levels. Furthermore, inflammatory reactions, which often involve macrophage recruitment, result in reductions in the interstitial edema (Hedger et al 2005) that appears to be a major factor blocking spermatogonial differentiation in irradiated rat testes (Porter et al 2006). Thus, the mild chronic inflammatory reaction resulting from transplantation and colonization of donor Sertoli cells in abnormal locations could be responsible for the increase in spermatogonial differentiation, but the exact mechanism cannot yet be determined.…”

Effects of lipopolysaccharide-induced inflammation on hypoxia and inflammatory gene expression pathways of the rat testis

“…In vivo and in vitro models involving the administration of lipopolysaccharide (LPS), a major pathogenic component of the cell wall of Gram negative bacteria, is a common experimental approach to evaluate inflammatory responses [ 6 , 7 ]. Pathogen-specific recognition sensors, such as Toll-like receptors (TLR), have been identified in the testis and implicated in the physiology of Leydig, Sertoli and spermatogenic cells [ 8 , 9 ].…”