Androgen-Mediated Immune Function Is Altered by the Apolipoprotein E Gene

Abstract

Androgens, like estrogens, have been linked to neuroprotective effects in the brain and to the improvement of cognitive function. Part of this effect may be due to the action of androgens on the innate immune response. We have examined the action of dihydrotestosterone (DHT) and testosterone on immune activation in primary cultures of microglia, the central nervous system macrophage. Our data indicate that DHT acts as an antiinflammatory agent and depresses both nitric oxide and TNF␣ production in a dose-dependent fashion. However, testosterone treatment of microglia and peritoneal macrophages increased supernatant nitrite levels, indicative of a proinflammatory effect. Because the apolipoprotein E (APOE) genotype also dramatically impacts macrophage function and has been linked to neurodegenerative disease, we compared the effects of APOE genotype on androgen-mediated regulation of inflammation using targeted replacement mice expressing only the human APOE3 or human APOE4 gene. Our data show that the antiinflammatory activity of DHT is significantly reduced in APOE4 targeted replacement mice compared to APOE3 mice. The effect was not due to an APOE isoform-specific change in androgen receptor mRNA and protein expression. Rather, innate immune signaling pathways regulated by androgens are altered in the APOE4 microglia. Compared to APOE3 microglia, DHT treatment did not reduce the phosphorylation of p38 MAPK or p54/p56 Janus kinase in APOE4 mice. Thus, our data suggest that DHT modulation of kinase activity is altered in microglia from mice expressing an APOE4 genotype and may impact androgen treatment therapies in individuals with an APOE4 genotype. (Endocrinology 148: 3383-3390, 2007)

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought

“…Human studies also support a role of sex hormones in OA, showing increased OA prevalence and severity in postmenopausal women compared with premenopausal women and age-matched men 48,49 . Moreover, androgens and ApoE isoforms have been shown to be functionally intertwined in inflammatory processes 46,50 , providing a possible rationale as to why ApoE*3Leiden.CETP males show more cartilage degradation in response to metabolic challenges compared with females. Contrary to the males, female ApoE*3Leiden.CETP transgenic mice showed less cartilage degradation on chow but were susceptible to diet-induced OA.…”

Obesity and sex interact in the regulation of Alzheimer's disease

“…Experimental work in animal models has also found sex differences in this regard, with apoE4 being associated with a greater pro-inflammatory response in males but not in females (Colton et al, 2005), suggesting that apoE4 carrying males may have an exaggerated inflammatory response. In addition, female apoE4 mice are less responsive to the anti-inflammatory effects of 17-β-estradiol (Brown et al, 2008), and male apoE4 mice are less responsive to the anti-inflammatory effects of DHT (Brown et al, 2007). Thus, both male and female apoE4 carriers may be less responsive to the anti-inflammatory effects of sex steroid hormones (Brown et al, 2008; 2007).…”

Hypothalamic-Pituitary-Gonadal Axis Hormones and Male Rheumatoid Arthritis: Novel Perspectives

“…Testosterone has been reported to have immune suppressive effects 4,[8][9][10][11] . In the mouse, T reduces macrophage expression of toll-like receptor 4, a trigger for inflammation and innate immunity 8 .…”

“…Testosterone also stimulated apoptosis of human bone marrow-derived macrophages by a mechanism involving caspase-3, caspase-8, and poly(ADP-ribose) polymerase 10 . However, one study found opposing effects of T and dihydrotestosterone (DHT) in microglia, the central nervous system macrophage-like cell 11 . DHT acted as an antiinflammatory agent, depressing both nitric oxide and TNF-α levels.…”