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MIP-3α expression in macrophages is NOD dependent


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-κB (NF-κB). Upon NF-κB 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 (NOD2(WT)) and the NOD2 SNP13 variant (NOD2(L1007fsinsC)) 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 NOD2(WT) 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.

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-κB (NF-κB). Upon NF-κB 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 (NOD2(WT)) and the NOD2 SNP13 variant (NOD2(L1007fsinsC)) 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 NOD2(WT) 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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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:January 2012
Deposited On:04 Apr 2012 07:13
Last Modified:14 Jun 2016 07:29
Publisher:Karger
ISSN:0012-2823
Publisher DOI:https://doi.org/10.1159/000335423
PubMed ID:22286692

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