Emerging role for TNF-α in erectile dysfunction

Abstract

Introduction: A role for cytokines in the pathophysiology of erectile dysfunction (ED) has emerged. Cytokines induce genes that synthesize other peptides in the cytokine family and several mediators, such as prostanoids, leukotrienes, nitric oxide, bradykinin, reactive oxygen species, and platelet-activating factor, all of which can affect vascular function. Consistent with the fact that the cavernosal tissue is a complex extension of the vasculature, risk factors that affect the vasculature have been shown to affect cavernosal function as well. Accordingly, the penile tissue has been recognized as an early sentinel for atherosclerosis that underlies coronary artery disease and cardiovascular diseases (CVD).

Aim: To review the literature pertaining to the role of tumor necrosis factor-alpha (TNF-α) in ED.

Methods: PubMed search for pertinent publications on the role of cytokines, particularly TNF-α, in CVD and ED.

Main outcome measures: Clinical and experimental evidence demonstrates that TNF-α may play a role in ED.

Results: TNF-α has been shown to play an important role in CVD, mainly due to its direct effects on the vasculature. In addition, high levels of TNF-α were demonstrated in patients with ED. In this review, we present a short description of the physiology of erection and the cytokine network. We focus on vascular actions of TNF-α that support a role for this cytokine as a potential candidate in the pathophysiology of ED, particularly in the context of CVD. A brief overview of its discovery, mechanisms of synthesis, receptors, and its main actions on the systemic and penile vasculature is also presented.

Conclusions: Considering that ED results from a systemic arterial defect not only confined to the penile vasculature, implication of TNF-α in the pathophysiology of ED offers a humoral linking between CVD and ED.

Figure 1

Illustration demonstrates the sequential events in the activation of TNFR1 and TNFR2 receptors by tumor necrosis factor-alpha (TNF-α). Usually, TNFR1-associated death domain protein (TRADD) is the first recruited protein after TNFR1 receptor activation, which acts like an anchor of at least three additional mediators: receptor interaction protein 1 (RIP1), TNF-receptor-associated factor 2 (TRAF2), and Fas-associated death domain protein (FADD). TRAF2 stimulates antiapoptotic and inflammatory pathways, whereas FADD stimulates caspases inducing apoptotic and anti-inflammatory effects. TRAF2 is also recruited by TNFR2 receptor with TNF-receptor-associated factor 1 (TRAF1) causing inflammatory and antiapoptotic effects.

Figure 2

Graph demonstrates simultaneous increase in the levels of tumor necrosis factor-alpha (TNF-α), erectile dysfunction (ED) and coronary artery disease (CAD). Correlation between age and plasma TNF-α levels (straight line). The dashed line illustrates the correlation between the incidence of ED and age. The age range for the first clinical symptoms of CAD is indicated by the shaded area. Adapted results from references [70,75,80-82].

Figure 3

Molecular mechanisms targeted by tumor necrosis factor-alpha (TNF-α) causing impairment of relaxation in the corpora cavernosa. During sexual arousal or sleep-related tumescence acetylcholine and nitric oxide (NO) are released from parasympathetic and nonadrenergic noncholinergic (NANC) nerves, respectively. Whereas acetylcholine causes NO generation by endothelial nitric oxide synthase (eNOS) activation on endothelial cells, neuronal nitric oxide synthase (nNOS) is responsible for NO production in NANC nerves. Upon its release, NO diffuses locally into adjacent smooth muscle cells of the corpus cavernosum and binds to soluble guanylyl cyclase, which catalyzes the conversion of guanosine trisphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP). TNF-α decreases eNOS and nNOS expression on endothelial cells and NANC nerves, respectively, causing impairment of cavernosal relaxation. Pro-inflammatory status is evoked by TNF-α, which induces adhesion molecules, nuclear factor-kappa B (NF-κB) and increases leukocyte migration. TNF-α induces changes in extracellular matrix deposition by smooth muscle cells and initiates a fibrotic state with reduced elasticity and compliance, which finally can lead to the impairment of erectile responses.

Figure 4

Molecular mechanisms activated by tumor necrosis factor-alpha (TNF-α) which causes hypercontractility of cavernosal smooth muscle cells. Norepinephrine release from sympathethic nerve terminals activates α-adrenergic receptors that lead to the subsequent activation of specific G proteins and phospholipase C (PLC), which causes a rise in the concentration of cytoplasmic Ca²⁺. Increased intracellular Ca²⁺ then activates myosin light chain (MLC) and triggers smooth muscle contraction and subsequent penile flaccidity. Activation of Ras homolog gene family member A (RhoA) which is facilitated by guanosine nucleotide exchange factors (GEFs), stimulates downstream effectors, such as Rho-kinase. Activated Rho-kinase phosphorylates the regulatory subunit of myosin light chain phosphatase and inhibits its activity, thus facilitating smooth muscle cells contraction and flaccidity. TNF-α increases sympathetic- and α-adrenergic agonist-mediated contractions in corpora cavernosa and activates the RhoA/Rho-kinase signaling pathway.