Tumor-free heart repair

Men are less prone to autoimmunity than women thanks to the anti-inflam-matory effect of male sex hormones. But how these androgens, such as testos-terone, exert this effect was a mystery. Dunn and colleagues now report on page 321 that a nuclear hormone receptor that gets boosted by testosterone switches off pro-inflammatory cytokine production in male CD4 + T cells. Androgens are known to shift the balance from pro-inflammatory Th1 cytokines to anti-inflammatory Th2 cyto-kines. Thus, a testosterone shot is all it takes to suppress lupus and diabetes symptoms in mice. " The link between androgens and protection against auto-immunity 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)-α. Expression of PPAR-α 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-α increased disease severity and expression of pro-inflammatory IFNγ and TNF by CD4 + T cells. In females, EAE was severe and cytokine production high in both wild-type and PPAR-α knockouts. The team showed that PPAR-α suppresses the production of IFNγ and TNF by preventing transcription factors NF-κB and c-Fos from binding to the promoters of these cytokine genes. Steinman's group is now examining PPAR-α expression in humans. If PPAR-α does show a gender-dependent dichotomy in people, they plan to test a known PPAR-α agonist along with androgen therapy in clinical trials for MS. Tissue regeneration without tumor formation may soon be within reach, at least for heart repair. On page 405, Behfar et al. report that embryonic stem (ES) cells preprogrammed to mature into cardiomyocytes can fix injured hearts in vivo without seeding tumors. Directing ES cells to become a particular tissue type in vivo is an inefficient process. Consequently, transplanted ES cell populations may give rise to tumors in recipient hosts. Behfar et al. reasoned that delivery of partially differentiated ES cells may result in safe outcome provided that a modulator of differentiation shuts down troublesome tumor pathways. When ES cells are delivered …