The mammalian testis is an immunologically privileged site whereby tight junctions between Sertoli cells typically segregate germ cell autoantigens within the adluminal and luminal compartments of the seminiferous tubules [1
]. Proinflammatory cytokines and other immune modulators must be tightly regulated in order to prevent inflammatory and immune responses in the testis. This review will focus on the localization and functional roles of tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1) in the mammalian testis and described two pathological conditions of the testis where a role for the proinflammatory cytokines has been determined.
TNFα is a multifunctional cytokine with effects not only in the proinflammatory response [2
] but in immunoregulatory responses [3
], and apoptosis [4
]. TNFα is produced in numerous cell types and is initially synthesized as a transmembrane precursor that undergoes proteolytic cleavage from the cell surface to a soluble monomer of 17 kDa [5
]. Soluble or secreted TNFα forms biologically active homotrimers; however, trimerization of TNFα may also occur with other members of the TNF protein family forming membrane-anchored heterotrimers that are also biologically active [6
Two families of TNFα receptors (TNFR) have been highly characterized. The TNFR type 1 family includes TNFR1 (p55TNFR; CD120a), Fas (CD95), death receptor (DR)3, DR4, DR5, and DR6 [7
]. The type 1 TNFRs are known for their ability to induce cell death via an amino acid motif in their cytoplasmic domains termed the death domain (DD) [7
]. Upon ligand binding to the TNFR1 the intracellular adaptor protein TRADD (TNFR-associated death domain protein) is recruited to the DD of the receptor. TRADD can then recruit FADD (Fas-associated death domain protein) ultimately leading to the activation of caspases and cell death [7
]. Alternatively, TRADD bound to TNFR1 can lead to the recruitment of cIAP (cellular inhibitor of apoptosis) or RIP (receptor interacting protein) enabling the binding of TRAF-2 (TNFR-associated factor-2). This complex formation does not result in apoptosis but rather leads to the activation of the NFκB pathway and/or the activation of the mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK) or p38 [7
]. Thus TNFR1 has dual signaling capabilities for either cell death or cell survival. Which pathway is selected appears to be a function of the adaptor proteins.
The TNFR type 2 family includes the TNFR2 (p75TNFR; CD120b), CD30, CD40, lymphotoxin receptor, RANK, and BAFF. The intracellular domains of these receptors do not contain DD but contain domains that associate with different TRAFs leading to the activation of cell signaling events [7
The IL-1family of peptides consists of three gene products, IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1Ra) [9
]. Both IL-1α and IL-1β are secreted by macrophages and have been termed the 'alarm cytokines'. They are pleiotropic cytokines with many well characterized effects on immune responses [10
]. Both IL-1α and IL-1β are known to cause inflammation and induce the expression of proinflammatory peptides such as inducible nitric oxide synthase, cyclooxygenase 2, IL-6, and TNFα [10
]. In fact, IL-1α, IL-1β, and TNFα stimulate their own as well as each other's production in an amplification loop [10
Both IL-1α and IL-1β are initially synthesized as precursors of 31 kDa that get proteolytically processed to their mature, 17 kDa forms [12
]. IL-1α is processed by calpain while IL-1β is processed by IL-1β-converting enzyme also know as caspase-1 [12
]. IL-1α and IL-1β differ from other cytokines in that they lack a signal sequence and cannot pass through the endoplasmic reticulum (ER) and Golgi apparatus. Their mechanism of secretion is not completely understood [13
]. On the other hand, IL-1Ra does have a signal sequence and is secreted by the well characterized ER-Golgi pathway [14
Two receptors have been described, IL-1 type I receptor (IL-1RI) and IL-1 type II receptor (IL-1RII), both receptors bind IL-1α and IL-1β and both receptors have reported to be expressed on many cell types. The IL-1RI is a signaling receptor. Following ligand binding to the receptor a protein termed IL-1R acceptor protein is recruited to the complex. This complex then triggers the activation of IL-1 receptor-associated kinase (IRAK) which ultimately leads to gene activation [15
]. On the other hand, IL-1RII is a non-signaling receptor that has been reported to be a decoy receptor [16
]. Therefore, ligand binding to signaling IL-1 receptor, IL-1RI, may be regulated by the binding of ligand to IL-1RII or can be blocked by the binding of IL-1Ra to the IL-1RI. To add yet another level of complexity both receptors may be released from the cell surface and bind soluble ligand [17
]. Both the IL-1 and TNFα signaling pathways can be stimulated under normal and pathological conditions in the testis.
Testicular torsion is characterized by a twisting of the spermatic cord that renders the testis ischemic. Surgical intervention is usually necessary for counter-rotation of the testis and reperfusion of the tissue [18
]. In rodent models of testicular torsion there is an increase in neutrophils to the testis that is associated with oxidative stress and germ cell-specific apoptosis [19
]. Recent data has demonstrated an increase in TNFα and IL-1β expression after reperfusion of the testis and that IL-1β may be responsible for stimulating a stress-related kinase signaling pathway leading to neutrophil recruitment from the testicular vasculature [22
]. Another testicular pathology is autoimmune orchitis which occurs in several species. In humans several idiopathic diseases have been described that are similar to autoimmune orchitis, and these diseases are associated with male infertility [23
]. In an animal model system termed experimental autoimmune orchitis (EAO) TNFα production by testicular T lymphocytes [24
] and macrophages [25
] has been linked to progression of the disease. Understanding the roles of proinflammatory cytokines in the testis and in testicular pathologies will aid in the development of therapies to rescue the testis from the adverse effects of inflammation and will give insights into male infertility.