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Heme mediated STAT3 activation in severe malaria.

Liu M, Amodu AS, Pitts S, Patrickson J, Hibbert JM, Battle M, Ofori-Acquah SF, Stiles JK - PLoS ONE (2012)

Bottom Line: Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.

ABSTRACT

Background: The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated.

Methods: We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.

Results: The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.

Conclusion: Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.

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ECM is associated with high levels of CXCL10 expression in vital organs in C57BL/6 WT mice.Left panel: CXCL10 messenger RNA (mRNA) expression in kidney, brain, and lung as determined by quantitative RT-PCR. Data are shown as mean ± SD (n = 6 per group). *P<0.05; ** P<0.01. ECM onset in C57BL/6 mice infected with P. berghei ANKA reveals that levels of CXCL10 mRNA were much higher in kidney, brain and lung tissues in infected than uninfected mice on day 4 and day 8 respectively (left panel). Right panel (Figure 6A–6F): representative examples of HO-1 immunohistochemistry staining in kidney, brain and lung of C57BL/6 wild type mice. Membrane and cytoplasma staining of CXCL10 protein were much stronger in the kidney, brain and lung of PBA infected WT C57 BL/6 mice compared to corresponding controls (Figure 6B vs. 6A, 6D vs. 6C, 6F vs.6E).
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pone-0034280-g006: ECM is associated with high levels of CXCL10 expression in vital organs in C57BL/6 WT mice.Left panel: CXCL10 messenger RNA (mRNA) expression in kidney, brain, and lung as determined by quantitative RT-PCR. Data are shown as mean ± SD (n = 6 per group). *P<0.05; ** P<0.01. ECM onset in C57BL/6 mice infected with P. berghei ANKA reveals that levels of CXCL10 mRNA were much higher in kidney, brain and lung tissues in infected than uninfected mice on day 4 and day 8 respectively (left panel). Right panel (Figure 6A–6F): representative examples of HO-1 immunohistochemistry staining in kidney, brain and lung of C57BL/6 wild type mice. Membrane and cytoplasma staining of CXCL10 protein were much stronger in the kidney, brain and lung of PBA infected WT C57 BL/6 mice compared to corresponding controls (Figure 6B vs. 6A, 6D vs. 6C, 6F vs.6E).

Mentions: Levels of CXCL10 mRNA (Figure 6, left panel) were much higher in kidney, brain and lung tissues in infected than uninfected mice on day 4 and day 8 respectively. The similar results were further confirmed by immunohistochemistry analysis as shown in the right panel of Figure 6. The membrane and cytoplasma staining of CXCL10 protein were much stronger in the kidney, brain and lung of PBA infected WT C57 BL/6 mice compared to corresponding controls (Figure 6B vs. 6A, 6D vs. 6C, 6F vs.6E). These data indicate that fatal ECM is associated with high levels of CXCL10 expression in vital organs in C57BL/6 WT mice.


Heme mediated STAT3 activation in severe malaria.

Liu M, Amodu AS, Pitts S, Patrickson J, Hibbert JM, Battle M, Ofori-Acquah SF, Stiles JK - PLoS ONE (2012)

ECM is associated with high levels of CXCL10 expression in vital organs in C57BL/6 WT mice.Left panel: CXCL10 messenger RNA (mRNA) expression in kidney, brain, and lung as determined by quantitative RT-PCR. Data are shown as mean ± SD (n = 6 per group). *P<0.05; ** P<0.01. ECM onset in C57BL/6 mice infected with P. berghei ANKA reveals that levels of CXCL10 mRNA were much higher in kidney, brain and lung tissues in infected than uninfected mice on day 4 and day 8 respectively (left panel). Right panel (Figure 6A–6F): representative examples of HO-1 immunohistochemistry staining in kidney, brain and lung of C57BL/6 wild type mice. Membrane and cytoplasma staining of CXCL10 protein were much stronger in the kidney, brain and lung of PBA infected WT C57 BL/6 mice compared to corresponding controls (Figure 6B vs. 6A, 6D vs. 6C, 6F vs.6E).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3316628&req=5

pone-0034280-g006: ECM is associated with high levels of CXCL10 expression in vital organs in C57BL/6 WT mice.Left panel: CXCL10 messenger RNA (mRNA) expression in kidney, brain, and lung as determined by quantitative RT-PCR. Data are shown as mean ± SD (n = 6 per group). *P<0.05; ** P<0.01. ECM onset in C57BL/6 mice infected with P. berghei ANKA reveals that levels of CXCL10 mRNA were much higher in kidney, brain and lung tissues in infected than uninfected mice on day 4 and day 8 respectively (left panel). Right panel (Figure 6A–6F): representative examples of HO-1 immunohistochemistry staining in kidney, brain and lung of C57BL/6 wild type mice. Membrane and cytoplasma staining of CXCL10 protein were much stronger in the kidney, brain and lung of PBA infected WT C57 BL/6 mice compared to corresponding controls (Figure 6B vs. 6A, 6D vs. 6C, 6F vs.6E).
Mentions: Levels of CXCL10 mRNA (Figure 6, left panel) were much higher in kidney, brain and lung tissues in infected than uninfected mice on day 4 and day 8 respectively. The similar results were further confirmed by immunohistochemistry analysis as shown in the right panel of Figure 6. The membrane and cytoplasma staining of CXCL10 protein were much stronger in the kidney, brain and lung of PBA infected WT C57 BL/6 mice compared to corresponding controls (Figure 6B vs. 6A, 6D vs. 6C, 6F vs.6E). These data indicate that fatal ECM is associated with high levels of CXCL10 expression in vital organs in C57BL/6 WT mice.

Bottom Line: Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.

ABSTRACT

Background: The mortality of severe malaria [cerebral malaria (CM), severe malaria anemia (SMA), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)] remains high despite the availability associated with adequate treatments. Recent studies in our laboratory and others have revealed a hitherto unknown correlation between chemokine CXCL10/CXCR3, Heme/HO-1 and STAT3 and cerebral malaria severity and mortality. Although Heme/HO-1 and CXCL10/CXCR3 interactions are directly involved in the pathogenesis of CM and fatal disease, the mechanism dictating how Heme/HO-1 and CXCL10/CXCR3 are expressed and regulated under these conditions is still unknown. We therefore tested the hypothesis that these factors share common signaling pathways and may be mutually regulated.

Methods: We first clarified the roles of Heme/HO-1, CXCL10/CXCR3 and STAT3 in CM pathogenesis utilizing a well established experimental cerebral malaria mouse (ECM, P. berghei ANKA) model. Then, we further determined the mechanisms how STAT3 regulates HO-1 and CXCL10 as well as mutual regulation among them in CRL-2581, a murine endothelial cell line.

Results: The results demonstrate that (1) STAT3 is activated by P. berghei ANKA (PBA) infection in vivo and Heme in vitro. (2) Heme up-regulates HO-1 and CXCL10 production through STAT3 pathway, and regulates CXCL10 at the transcriptional level in vitro. (3) HO-1 transcription is positively regulated by CXCL10. (4) HO-1 regulates STAT3 signaling.

Conclusion: Our data indicate that Heme/HO-1, CXCL10/CXCR3 and STAT3 molecules as well as related signaling pathways play very important roles in the pathogenesis of severe malaria. We conclude that these factors are mutually regulated and provide new opportunities to develop potential novel therapeutic targets that could be used to supplement traditional prophylactics and treatments for malaria and improve clinical outcomes while reducing malaria mortality. Our ultimate goal is to develop novel therapies targeting Heme or CXCL10-related biological signaling molecules associated with development of fatal malaria.

Show MeSH
Related in: MedlinePlus