s of Heme and mediating anti-inflammatory and anti-apoptotic functions. HO-1 induced by reactive oxygen species and nitric oxide, has recently been shown to STAT3 Activation in Severe Malaria be involved in regulation of angiogenesis. HO-1 may facilitate the repair of injured tissues through inhibition of infiltrating inflammatory cells. Severe malaria is associated with perturbation of inflammatory cytokines, chemokines, antiinflammatory cytokines and angiopoietic factors. Chemokine CXCL10 is a cytokine belonging to the CXC chemokine family. CXCL10 binds CXCR3 receptor to induce chemotaxis, apoptosis, cell growth and angiostasis. It is expressed early in mice infected with P. berghei ANKA as well as in human CM. Studies conducted in India and Ghana have identified CXCL10 as a serological marker highly linked with increased risk of fatal P. falciparum-mediated CM mortality in humans. Following our report of a role of CXCL10 in fatal human CM, several groups utilized gene knockout mice in ECM to confirm and demonstrate the role of CXCL10/CXCR3 interactions in the pathogenesis of fatal CM via the recruitment and activation of pathogenic CD8 T cells. In fact, survival of mice infected with the lethal strain of P. berghei ANKA CM increased to 80% in CXCL102/2 and CXCR32/2 mice when compared with the wild type within the observation period of 1012 days post infection. In addition to genetic deletion of CXCL10 gene, Nie et al also reported that CXCL10 neutralization with specific antibodies protected against cerebral malaria infection and inflammation. Passive transfer of anti-CXCL10 antibodies reduced the recruitment of inflammatory 1727499
leukocytes across the blood brain barrier, while genetic deletion of ” CXCL10 not only alleviated intravascular inflammation but also reduced pRBC sequestration in the brain. Not surprisingly, adoptive transfer of CD8 cells abrogated protection of CM in CXCR32/2 mice. In addition, NK cells mediate direct cytotoxic activity or reconstitution of capacity of T cells to migrate in response to CXCL10 to the central nervous system in CM. Thus, the relationship between over production of Heme, CXCL10/CXCR3, and related signaling mechanisms and fatal CM needs clarification. The signal transducer and activator of transcription is a signaling molecule which can be activated by pro- and antinflammatory stimuli and cellular stresses, therefore STAT3 can be either pro-inflammatory and anti-inflammatory. Many cytokines can activate STAT3, for instance, STAT3 is MedChemExpress Relebactam essential for the function of both interleukin-6 and IL-10, whereas IL-6 is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Among the cytokines ” activating STAT3, only IL-10 activates the anti-inflammatory pathway that is STAT3dependent. Opposing roles of IL-6 and IL-10 mediated by STAT3 might be explained by selective blocking IL-6 and IL-10 signaling by suppressor of cytokine signaling recruitment, which is part of the STAT3 negative-feedback loop. SOCS3 is a relatively specific inhibitor of gp130, and is a key regulator of IL-6 and IL-10. SOCS3 selectively blocks signaling by IL-6, specifically prevents activation of STAT3 by IL-6 but not IL-10, thereby preventing its ability to inhibit lipopolysaccharide -induced anti-inflammatory signaling. Thus in the absence of SOCS3 in macrophages, the action of IL-6 shifted from inducing a pro-inflammatory responses to a STAT3-mediated anti-inflammatory response. STAT3 protein locates in the cytoplasm in an ina