title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland. martin.hausmann@usz.ch
authors.forename: M
authors.initials: M
authors.lastname: Hausmann
authors.forename: C
authors.initials: C
authors.lastname: Zeitler
authors.forename: A
authors.initials: A
authors.lastname: Weber
authors.forename: M
authors.initials: M
authors.lastname: Krebs
authors.forename: S
authors.initials: S
authors.lastname: Kellermeier
authors.forename: P
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: C
authors.initials: C
authors.lastname: de Vallière
authors.forename: K
authors.initials: K
authors.lastname: Kosovac
authors.forename: M
authors.initials: M
authors.lastname: Fried
authors.forename: E
authors.initials: E
authors.lastname: Holler
authors.forename: G
authors.initials: G
authors.lastname: Rogler
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D054418:Chemokine CCL20 / Q000378:metabolism*; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D055815:Young Adult
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D017931:DNA Primers; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D000119:Acetylmuramyl-Alanyl-Isoglutamine