Brain inflammation (blue) is more severe in the absence of the testosterone-responsive receptor PPAR.

Androgens are known to shift the balance from pro-inflammatory Th1 cytokines to anti-inflammatory Th2 cytokines. Thus, a testosterone shot is all it takes to suppress lupus and diabetes symptoms in mice. "The link between androgens and protection against autoimmunity could not be clearer," says senior author Larry Steinman. "But we still had to figure out how androgens actually instruct T cells to stop attacking the host."

A good candidate was the nuclear hormone receptor peroxisome proliferator activated receptor (PPAR)-. Expression of PPAR- was previously shown to increase in response to testosterone and to be higher in male compared with female hepatocytes. The team now shows that this gender difference extends to T cells and that it affects their inflammatory activities.

The group tested mice with experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). In the male mice, knocking out PPAR- increased disease severity and expression of pro-inflammatory IFN and TNF by CD4⁺ T cells. In females, EAE was severe and cytokine production high in both wild-type and PPAR- knock-outs.

The team showed that PPAR- suppresses the production of IFN and TNF by preventing transcription factors NF-B and c-Fos from binding to the promoters of these cytokine genes.

Steinman's group is now examining PPAR- expression in humans. If PPAR- does show a gender-dependent dichotomy in people, they plan to test a known PPAR- agonist along with androgen therapy in clinical trials for MS.