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World J Gastroenterol. Dec 14, 2007; 13(46): 6191-6196
Published online Dec 14, 2007. doi: 10.3748/wjg.v13.i46.6191
Heterozygous nucleotide-binding oligomerization domain-2 mutations affect monocyte maturation in Crohn’s disease
Marilena Granzotto, Elisa Fabbro, Massimo Maschio, Stefano Martelossi, Sara Quaglia, Alberto Tommasini, Gianni Presani, Alessandro Ventura
Marilena Granzotto, Stefano Martelossi, Alberto Tommasini, Gianni Presani, Alessandro Ventura, Institute for Child Health Burlo Garofolo, Trieste 34137, Italy
Elisa Fabbro, Massimo Maschio, Sara Quaglia, Alberto Tommasini, Alessandro Ventura, Department of Sciences of Reproduction and Development, University of Trieste, Trieste, Italy
Author contributions: All authors contributed equally to the work.
Supported by the Italian Ministry of Health, No. 150/03
Correspondence to: Dr. Marilena Granzotto, Laboratory of Immunology, Institute of Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste 34137, Italy. granzotto@burlo.trieste.it
Telephone: +39-40-3785216 Fax: +39-40-3785210
Received: March 21, 2007
Revised: August 25, 2007
Accepted: September 16, 2007
Published online: December 14, 2007

AIM: To investigate the function of monocytes in Crohn’s disease (CD) patients and to correlate this with disease-associated nucleotide-binding oligomerization domain-2 (NOD2) gene variants.

METHODS: Monocytes from 47 consecutively referred CD patients and 9 healthy blood donors were cultured with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and stimulated with lipopolysaccharide (LPS) or muramyldipeptide (MDP), the putative ligand of NOD2.

RESULTS: We found that monocytes from CD patients differentiated in vitro to mature dendritic cells (DCs), as determined by immunophenotype and morphology. NOD2 genotype was assessed in all subjects, and we observed high CD86 expression on immature and LPS-stimulated DCs in NOD2 mutated CD patients, as compared with wtNOD2 CD patients and controls. By contrast, CD86 expression levels of DCs induced to maturity with MDP derived from NOD2-mutated subjects were comparable to those of normal subjects. The amount of IL-12p70 in patient-cell cultures was larger than in controls after LPS treatment, but not after treatment with MDP.

CONCLUSION: Our results suggest that DCs obtained from patients with mutations in the NOD2 gene display an activated phenotype characterized by high CD86 expression, but have a diminished response to MDP when compared to the terminal differentiation phase. We speculate that the altered differentiation of monocytes might lead to an imbalance between inflammation and the killing ability of monocytes, and may be relevant to the pathogenesis of CD.

Keywords: Crohn’s disease, Dendritic cells, Immun-ophenotype, Muramyldipeptide, Nucleotide-binding oligomerization domain-2