Testosterone as a regulator of immune system via modulation of toll-like receptor 4/extracellular signal-regulated kinase signaling pathway

Chien‐Wei Chen ,Sindy Hu ,Paulus S Wang ,Shyi-Wu Wang

doi:10.14800/ics.1407

Abstract

There is a growing body of evidence supporting the immunomodulation effects of testosterone. Previous researches have focused on its direct blunt inflammatory effect on mediation of cytokines secretion through down-regulated expression of toll-like receptor 4 (TLR4). However, how testosterone modulates immune responses via mechanisms of TLR4 downstream molecules has not yet been elucidated. Recently, we have firstly confirmed that testosterone deficiency is the main reason that caused the exacerbate inflammation status in rat spleen. Orchidectomy in rats resulted in a markedly enhance of spleen weight ( splenomegaly ) and basal production of nitric oxide (NO) from splenocytes. Moreover, lipopolysaccharide (LPS) amplified proliferation rate of splenocytes and the production of tumor necrosis factor-alpha (TNF-α) following castration. Extracellular signal-regulated kinase (ERK) is a critical mediator of TLR4 cascades, and we further examined whether absence of endogenous testosterone affects ERK expression. As anticipated, orchidectomized rats manifested an increased phosphorylation of ERK. Furthermore, testosterone administration was demonstrated to be associated with a diminished LPS-evoked TNF-α and NO secretion in a dose-dependent manner. In the present study, we answered how testosterone withdrawal affects downstream signaling cascades of TLR4 and supports that testosterone might potentially ameliorate inflammatory responses. Our findings mention the possibility that testosterone functions might serve as a useful endogenous regulator of immune responses.

Highlights

Signaling on consequence of inflammatory response in orchidectomized rats [13]
Emerging studies have revealed that testosterone levels are inversely correlated with a number of inflammatory mediators, e.g. C-reactive protein, interleukin-1β, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) [6,7,8,9] in humans
The concept of testosterone regulating Toll-like receptor 4 (TLR4) have been first suggested by Rettew who demonstrated that testosterone withdrawal increases inflammation as assessed by TNF-α and IL-6 concentrations after high expression of TLR4 on macrophage in orchidectomized mouse [10]

Summary

Introduction

Signaling on consequence of inflammatory response in orchidectomized rats [13]. testosterone propionate replacement restored the above results in castrated rats [13]. Many studies aimed to demonstrate the causality of relationship between testosterone and anti-inflammatory response, how testosterone regulates actual mechanism of immune responses has not yet been elucidated. Block of TLR4 activity can prevent excessive inflammation and consequent development of immune-related diseases.

Results

Conclusion