ssue damage, Heme/ HO-1 and CXCL10 are involved in the pathogenesis of CM and that the level of free Heme correlates with PBA infection in mice, Expression of HO-1 in tissues may be protective against Heme and 10670419” PBA induced damage, High levels of CXCL10 is associated with ECM onset in PBA infected mice, STAT3 is activated by PBA infection in vivo and Heme in vitro, Heme upregulates HO-1 and CXCL10 production trough STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro, HO-1 transcription is positively AZ-6102 web regulated by CXCL10, HO-1 regulates STAT3 signaling. Taken together, our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in inflammation and organ damage in the pathogenesis of severe malaria. Heme and HO-1 interaction moved center stage in cerebral malaria research in 2007, when Mota’s group reported that HO-1 and carbon monoxide suppress the pathogenesis of ECM. HO-1 was then found to be capable of inhibiting vascular occlusion in transgenic sickle cell mice . From these studies it seems that the ability of individuals to respond to increase in Heme by producing HO-1 may be a crucial endogenous protective factor. However, some other studies have refuted the findings that HO-1 protects the development of CM. These studies suggests that the frequency of short n alleles, which may lead to high level of HO-1, is markedly higher in CM patients. Moreover, liver stages of the Plasmodium 15256538” was markedly reduced in Hmox12/2 mice. These conflicting results suggest that the regulated expression of HO-1 is quite complex in different tissues at different stages of the Plasmodium life cycle. Therefore, further experimental and epidemiological studies are necessary to unveil the role of Heme and HO-1 interactions in severity of malaria. HO-1 is a heat shock protein, which is an integral membrane protein of the smooth endoplasmic reticulum, and is the only inducible isoform of HO. The expression of HO-1 occurs at low levels in most tissues under physiological conditions. HO-1 can localize STAT3 Activation in Severe Malaria to distinct subcellular compartments. Inducible HO activity appeared in plasma membrane, cytosol, mitochondria, isolated caveolae and nucleus in cell culture models. Early studies indicate that HO-1 in mitochondria and caveolae performs important biological and physiological actions, although the function of HO-1 in caveolae and nucleus is not completely 7 
STAT3 Activation in Severe Malaria understood. The nuclear form of HO-1 serves potentially as a transcriptional regulator. Under conditions of hypoxia, hemin or Heme-hemopexin, HO-1 translocates to the nucleus. Nuclear translocation compromises the HO activity, but nuclear localization of HO-1 protein functions to up-regulate genes that promote cytoprotection against oxidative stress. Our data showed that levels of HO-1 were significantly increased in plasma and tissues, the activated HO-1 protein was mostly located in the nucleus, which supports the hypothesis that HO-1 protects against Heme and tissue damage. In CXCL102/2 mice, PBA infection caused modest increase in HO-1 mRNA, but not in HO-1 protein, there could be a number of reasons. HO-1 protein may be expressed but at levels below detectable limits, or may be rapidly degraded. As protein expression reflects functional adaption observed in species phenotype, HO-1 in either case probably did not exert the expected protection. Consider
