Sterile inflammatory insults are known to activate innate immunity and propagate organ damage through the recognition of extracellular Damage Associated Molecular Pattern (DAMP) molecules. Although DAMPs, such as endogenous DNA and nuclear High Mobility Group Box 1, have been shown to be critical in sterile inflammation, the role of nuclear histone proteins has not yet been investigated. We report that endogenous histones function as DAMPs following ischemic injury through the pattern recognition receptor Toll-Like Receptor 9 (TLR9) to initiate inflammation. Using an in vivo model of hepatic ischemia/reperfusion (I/R) injury, we show that levels of circulating histones are significantly higher after I/R, and that histone neutralization significantly protects against injury. Injection of exogenous histones exacerbates I/R injury through cytotoxic effects mediated by TLR9 and MyD88. In addition, histone administration increases TLR9 activation, while neither TLR9 nor MyD88 mutant mice respond to exogenous histones. Furthermore, we demonstrate in vitro that extracellular histones enhance DNA-mediated TLR9 activation in immune cells through a direct interaction. Conclusions these novel findings reveal that histones represent a new class of DAMP molecules and they serve as a crucial link between initial damage and activation of innate immunity during sterile inflammation.

High expression of estrogen receptor a (ERa) is associated with a poor prognosis that correlates closely with cellular proliferation in breast cancer. However, the exact molecular mechanism by which ERa controls breast cancer cell proliferation is not clear. Here we report that ERa regulates the cell cycle by suppressing p53/p21 and up-regulating proliferating cell nuclear antigen (PCNA) and proliferation-related Ki-67 antigen (Ki-67) to promote proliferation of MCF-7 cells. In addition, 17-b-estradiol (E2) enhances ERa-induced proliferation of MCF-7 cells by stimulating expression of PCNA and Ki-67. Knockdown of ERa significantly affects PCNA/ Ki-67 and p53/p21 expression. Furthermore, ERa inhibits the transcriptional activity of p53/p21 in an estrogen response element-dependent manner. More importantly, we provide new evidence that ERa mediates proliferation of MCF-7 cells by up-regulating miR-17 to silence the expression of p21. Thus, these data provide new insights into the underlying effect of ERa on breast cancer proliferation.

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Background:The JAK-STAT3 signaling pathway is one of the critical pathways regulating cell proliferation and differentiation. Results: Knockdown of endogenous STAT3 enhances VSMC contractile phenotype by promoting the association of the myocardin-SRF-CArG complex. Conclusion:The JAK-STAT3 signaling pathway is a central regulator of the phenotypic switch of VSMCs. Significance: The phenotypic switch of VSMCs can be controlled by modulation of JAK-STAT3 signaling.