A Myeloid Hypoxia-inducible Factor 1 alpha-Kruppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis

作者：Mahabeleshwar Ganapati H^*; Qureshi Muhammad Awais; Takami Yoichi; Sharma Nikunj; Lingrel Jerry B; Jain Mukesh K

来源：Journal of Biological Chemistry, 2012, 287(2): 1448-1457.

DOI：10.1074/jbc.M111.312702

Although Gram-positive infections account for the majority of cases of sepsis, the molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components of Gram-positive bacteria contribute to the development of sepsis. Experimental observations derived from cultured primary macrophages and the cell line indicate that Gram-positive bacterial endotoxins induce hypoxia-inducible factor 1 alpha (HIF-1 alpha) mRNA and protein expression. Inoculation of live or heat-inactivated Gram-positive bacteria with macrophages induced HIF-1 transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1 alpha attenuated Gram-positive bacterial endotoxin-induced cellular motility and proinflammatory gene expression in macrophages. Conversely, Gram-positive bacteria and their endotoxins reduced expression of the myeloid anti-inflammatory transcription factor Kruppel-like transcription factor 2 (KLF2). Sustained expression of KLF2 reduced and deficiency of KLF2 enhanced Gram-positive endotoxins induced HIF-1 alpha mRNA and protein expression in macrophages. More importantly, KLF2 attenuated Gram-positive endotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistent with these results, mice deficient in myeloid HIF-1 alpha were protected from Gram-positive endotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficient mice were susceptible to Gram-positive sepsis induced mortality and clinical symptoms. Collectively, these observations identify HIF-1 alpha and KLF2 as critical regulators of Gram-positive endotoxin-mediated sepsis.

• 出版日期2012-1-6