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MIP-3α Expression in Macrophages Is NOD Dependent

Hausmann M.a · Zeitler C.c · Weber A.b · Krebs M.a · Kellermeier S.a · Rosenstiel P.e · de Vallière C.a · Kosovac K.c · Fried M.a · Holler E.d · Rogler G.a
aDivision of Gastroenterology and Hepatology and bInstitute of Pathology, University Hospital of Zurich, Zurich, Switzerland; cDepartment of Internal Medicine I, University of Regensburg, dDepartment of Haematology/Oncology, University Medical Centre, Regensburg, and eInstitute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany Digestion 2012;85:192–201 (DOI:10.1159/000335423)

Abstract

Background: The first identified susceptibility gene for Crohn’s disease, NOD2, acts as a sensor for the bacterial-wall peptidoglycan fragment muramyl dipeptide (MDP) and activates the transcription factor nuclear factor-ĸB (NF-ĸB). Upon NF-ĸB activation, intestinal macrophages (IMACs) induce expression of macrophage inflammatory protein (MIP)-3α to attract memory T lymphocytes. We therefore investigated the influence of NOD2 ligation of IMAC differentiation and functional MIP-3α induction. Methods: Human embryonal kidney HEK293 cells were transfected with NOD2 wild-type (NOD2WT) and the NOD2 SNP13 variant (NOD2L1007fsinsC) and stimulated with MDP. Recruitment of CD45R0+ and Th17 cells was determined by immunohistochemistry. Results: Endogenous NOD2 stimulation was followed by a dose-dependent increase in MIP-3α secretion in MONO-MAC-6 (MM6) cells. MIP-3α mRNA was also significantly (* p < 0.05) induced in HEK293 transfected with NOD2WT via MDP ligation. In vivo cell-cell contacts between IMACs and CD45R0+ memory T cells as well as recruitment of Th17 cells in patients of NOD2 variants were unchanged as compared to wild-type patients. Conclusion: Our data demonstrate a dose-dependent increase in MIP-3α secretion in the human myeloid cell line MM6 upon MDP. However, MIP-3α-driven recruitment of Th17 cells or CD45R0+ memory T lymphocytes is not affected in patients carrying heterozygous NOD2 variants.

 

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