Tumour necrosis factor-  released by testicular macrophages induces apoptosis of germ cells in autoimmune orchitis

Abstract

Results demonstrated that soluble factors released from testicular EAO macrophages induce apoptosis of GC, biased by the local inflammatory environment, and that TNF-alpha is a relevant cytokine involved in testicular damage during severe orchitis.

Intratesticular Expression of mRNAs of Both Interferon γ and Tumor Necrosis Factor α is Significantly Increased in Experimental Autoimmune Orchitis in Mice

“…In immunohistochemical studies on testicular cytokines, it was revealed that testicular interstitial cells were positive for IFN-γ and TNF-α antibodies in EAO [7,19]. Enzyme-linked immunosorbent assays of testicular macrophages isolated from EAO-affected testes also demonstrated that these two cytokines were significantly secreted into the culture supernatant [8,9]. However, a real-time RT-PCR study of isolated dendritic cells obtained from TH+CFA+BP-EAOaffected testes did not show a significant change in TNF-α mRNA expression [20].…”

“…IFN-γ is produced by lymphocytes stimulated by antigenic substances and has the abilities of macrophage activation, induction of major histocompatibility antigens, T cell homing and regulation of cell proliferation [21,22]. TNF-α is a cytokine produced mainly by macrophages and has the ability to augment inflammatory responses involving cytotoxic effects including apoptosis on target cells [9,[23][24][25][26][27]. Moreover, it is noteworthy that these two cytokines are harmful to the seminiferous epithelium, resulting in spermatogenic disturbance.…”

“…It has also been reported that the disease can be suppressed in vivo by the administration of anti-TNF-α antibodies but not anti-IFN-γ antibodies [6]. In rat EAO induced by immunization with TH+CFA+BP, it was shown that isolated testicular macrophages secreted both IFN-γ and TNF-α [7][8][9]. However, the intratesticular changes in IFN-γ and TNF-α mRNA expression at the organ level have not yet been investigated in any EAO model.…”

Testicular defense systems: immune privilege and innate immunity

“…By contrast, circulating macrophages significantly infiltrate the testis in orchitis and are detrimental to spermatogenesis. 40,41 Clinical observation revealed high macrophage numbers in the testis of patients with aspermatogenesis and infertility indicating a negative correlation between circulating macrophages and spermatogenesis. 42 Dendritic cells (DCs) exist in the testicular interstitial spaces and represent a minor population of the interstitial cells in the normal testis, reaching one-tenth of the numbers of macrophages.…”

Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

“…In the later stages of the disease, these infiltrates can form granulomas. The final phase of EAO consists of the progressive apoptosis of germ cells, which leads to aspermatogenesis and thus sterility (16)(17)(18)(19)(20). Decreased levels of testosterone and increased FSH concentrations in serum indicate that the detrimental influence of EAO is not limited to testicular germ cells alone but also extends to the dysfunction of the somatic, Sertoli, and Leydig cells (21).…”