ALCOHOL INHIBITS UPREGULATION OF GBP7 EXPRESSION BY HEMATOPOIETIC STEM/PROGENITOR CELLS DURING THE GRANULOPOIETIC RESPONSE TO SEPTIC INFECTION

ALCOHOL INHIBITS UPREGULATION OF GBP7 EXPRESSION BY HEMATOPOIETIC STEM/PROGENITOR CELLS DURING THE GRANULOPOIETIC RESPONSE TO SEPTIC INFECTION

Shi X; Simms K J; Ewing T J; Zhang P

Alcoholism-Clinical and Experimental Research

2019

2019-06

Alcohol impairs activation of hematopoietic stem/progenitor cells (HSPCs) during the granulopoietic response to serious bacterial infection. This study investigated the involvement of guanylate‐binding protein 7 (GBP7) in the regulation of HSPC function during the granulopoietic response and the effect of alcohol on this signaling system. Male Balb/c mice were fed on Lieber‐DeCarli low fat liquid alcohol diet for 5 weeks. Binge alcohol administration was given to mice at the end of the 5‐week feeding by intraperitoneally (i.p.) injecting a single dose of alcohol (20% alcohol in saline, 5 g alcohol/kg). Pair‐fed mice on the control diet received an i.p. injection of saline. Septicemia was induced in mice via intravenous (i.v.) injection of E. coli (E11775, ATCC, Rockville, MD, ˜5 × 107 CFUs/mouse) 30 min after the binge alcohol intoxication. E. coli septicemia caused a markedly upregulation of GBP7 expression at both mRNA and protein levels in HSPCs. This upregulation of GBP7 expression was accompanied with activation of HSPCs. Chronic plus binge alcohol administration suppressed the upregulation of GBP7 expression along with inhibition of HSPC activation in response to E. coli septicemia. Searching murine GBP7 gene promoter region identified multiple Fos/Jun binding sites. Alcohol suppressed activation of c‐Jun N‐terminal kinases (JNK1/2) in marrow cells during E. coli septicemia. Inhibition of JNK1/2 activation with specific inhibitor (SP600125) suppressed lipopolysaccharide‐induced up‐regulation of GBP7 expression by HSPCs. The predominant localization of GBP7 was in the nuclei of HSPCs, which might imply its close association with nuclear signaling pathways driving cell cycling. Septicemia caused marked increases in cyclin D1 expression and enhancement of proliferation in HSPCs, both of which were suppressed by alcohol. Knockout of GBP7 gene in murine HSC line EML cells profoundly inhibited their proliferation as reflected by the marked decrease in cell BrdU incorporation. GBP7 gene knockout also significantly reduced granulocyte/monocyte colony‐formatting activity In EML cells. These results indicate that GBP7 plays an important role in the activation of HSPCs during the granulopoietic response. Alcohol disrupts GBP7 signaling, which may serve as a mechanism underlying the impairment of primitive hematopoietic precursor cell activation during the granulopoietic response to septic infection in hosts intoxicated with alcohol (Supported by NIH grant AA022816).

Substance Abuse

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101A–101A

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0145-6008