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* Molecular and Cellular Pathobiology Program, Children’s Memorial Research Center, Children’s Memorial Hospital, Chicago, IL 60614;
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
Severe sepsis is associated with dysfunction of the macrophage/monocyte, an important cellular effector of the innate immune system. Previous investigations suggested that probiotic components effectively enhance effector cell functions of the immune system in vivo. In this study, we produced bacteria-free, lysozyme-modified probiotic components (LzMPC) by treating the probiotic bacteria, Lactobacillus sp., with lysozyme. We showed that oral delivery of LzMPC effectively protected rats against lethality from polymicrobial sepsis induced by cecal ligation and puncture. We found that orally administrated LzMPC was engulfed by cells such as macrophages in the liver after crossing the intestinal barrier. Moreover, LzMPC-induced protection was associated with an increase in bacterial clearance in the liver. In vitro, LzMPC up-regulated the expression of cathelicidin-related antimicrobial peptide (CRAMP) in macrophages and enhanced bactericidal activity of these cells. Furthermore, we demonstrated that surgical stress or cecal ligation and puncture caused a decrease in CRAMP expression in the liver, whereas enteral administration of LzMPC restored CRAMP gene expression in these animals. Using a neutralizing Ab, we showed that protection against sepsis by LzMPC treatment required endogenous CRAMP. In addition, macrophages from LzMPC-treated rats had an enhanced capacity of cytokine production in response to LPS or LzMPC stimulation. Together, our data suggest that the protective effect of LzMPC in sepsis is related to an enhanced cathelicidin-related innate immunity in macrophages. Therefore, LzMPC, a novel probiotic product, is a potent immunomodulator for macrophages and may be beneficial for the treatment of sepsis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Excellence in Academic Medicine Award from Illinois Department of Public Aid (to X.-D.T.), Grant R01DK064240 (to X.-D.T.) from National Institutes of Health, and Eloise and Warren Batts Investigator Chair (to X.-D.T.). X.-L.Z. is a visiting scholar supported by Department of Gastroenterology, Qilu Hospital, Medical College of Shandong University, Jinan, Shandong, People’s Republic of China.
2 Address correspondence and reprint requests to Dr. Xiao-Di Tan, Molecular and Cellular Pathobiology Program, Children’s Memorial Research Center, Children’s Memorial Hospital, 2300 Children’s Plaza, Box 217, Chicago, IL 60614. E-mail address: xtan{at}northwestern.edu
3 Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; CRAMP, cathelicidin-related antimicrobial peptide; CLP, cecal ligation and puncture; DAPI, 4',6'-diamidino-2-phenylindole; LzMEcC, lysozyme-modified E. coli component; LzMPC, lysozyme-modified probiotic component; pAb, polyclonal Ab.
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