Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways

A Brosbøl-Ravnborg; C L Hvas; J Agnholt; J F Dahlerup; I Vind; A Till; P Rosenstiel; P Höllsberg

doi:10.1111/j.1365-2249.2008.03850.x

Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways

A Brosbøl-Ravnborg, C L Hvas, J Agnholt, J F Dahlerup, I Vind, A Till, P Rosenstiel, P Höllsberg

Department of Clinical Medicine

12 Citations (Scopus)

Abstract

Pattern recognition receptors (PRRs) are an integral part of the innate immune system and govern the early control of foreign microorganisms. Single nucleotide polymorphisms (SNPs) in the intracellular pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD2, nucleotide oligomerization domain 2) are associated with Crohn's disease (CD). We investigated the impact of NOD2 polymorphisms on cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) in response to Toll-like receptor (TLR) and NOD2 ligands. Based on NOD2 SNP analyses, 41 CD patients and 12 healthy controls were studied. PBMCs were stimulated with NOD2 and TLR ligands. After 18 h culture supernatants were measured using multiplex assays for the presence of human cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 beta and tumour necrosis factor (TNF)-alpha. In CD patients, TLR-induced GM-CSF secretion was impaired by both NOD2-dependent and -independent mechanisms. Moreover, TNF-alpha production was induced by a TLR-2 ligand, but a down-regulatory function by the NOD2 ligand, muramyl dipeptide, was impaired significantly in CD patients. Intracellular TLR ligands had minimal effect on GM-CSF, TNF-alpha and IL-1beta secretion. CD patients with NOD2 mutations were able to secrete TNF-alpha, but not GM-CSF, upon stimulation with NOD2 and TLR-7 ligands. CD patients have impaired GM-CSF secretion via NOD2-dependent and -independent pathways and display an impaired NOD2-dependent down-regulation of TNF-alpha secretion. The defect in GM-CSF secretion suggests a hitherto unknown role of NOD2 in the pathogenesis of CD and is consistent with the hypothesis that impaired GM-CSF secretion in part constitutes a NOD2-dependent disease risk factor.

Original language	English
Journal	Clinical and Experimental Immunology
Volume	155
Issue number	3
Pages (from-to)	487-95
Number of pages	8
ISSN	0009-9104
DOIs	https://doi.org/10.1111/j.1365-2249.2008.03850.x
Publication status	Published - 2008

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10.1111/j.1365-2249.2008.03850.x

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Brosbøl-Ravnborg, A., Hvas, C. L., Agnholt, J., Dahlerup, J. F., Vind, I., Till, A., Rosenstiel, P., & Höllsberg, P. (2008). Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways. Clinical and Experimental Immunology, 155(3), 487-95. https://doi.org/10.1111/j.1365-2249.2008.03850.x

Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways. / Brosbøl-Ravnborg, A; Hvas, C L; Agnholt, J et al.
In: Clinical and Experimental Immunology, Vol. 155, No. 3, 2008, p. 487-95.

Research output: Contribution to journal › Journal article › Research › peer-review

Brosbøl-Ravnborg, A, Hvas, CL, Agnholt, J, Dahlerup, JF, Vind, I, Till, A, Rosenstiel, P & Höllsberg, P 2008, 'Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways', Clinical and Experimental Immunology, vol. 155, no. 3, pp. 487-95. https://doi.org/10.1111/j.1365-2249.2008.03850.x

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title = "Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways",

abstract = "Pattern recognition receptors (PRRs) are an integral part of the innate immune system and govern the early control of foreign microorganisms. Single nucleotide polymorphisms (SNPs) in the intracellular pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD2, nucleotide oligomerization domain 2) are associated with Crohn's disease (CD). We investigated the impact of NOD2 polymorphisms on cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) in response to Toll-like receptor (TLR) and NOD2 ligands. Based on NOD2 SNP analyses, 41 CD patients and 12 healthy controls were studied. PBMCs were stimulated with NOD2 and TLR ligands. After 18 h culture supernatants were measured using multiplex assays for the presence of human cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 beta and tumour necrosis factor (TNF)-alpha. In CD patients, TLR-induced GM-CSF secretion was impaired by both NOD2-dependent and -independent mechanisms. Moreover, TNF-alpha production was induced by a TLR-2 ligand, but a down-regulatory function by the NOD2 ligand, muramyl dipeptide, was impaired significantly in CD patients. Intracellular TLR ligands had minimal effect on GM-CSF, TNF-alpha and IL-1beta secretion. CD patients with NOD2 mutations were able to secrete TNF-alpha, but not GM-CSF, upon stimulation with NOD2 and TLR-7 ligands. CD patients have impaired GM-CSF secretion via NOD2-dependent and -independent pathways and display an impaired NOD2-dependent down-regulation of TNF-alpha secretion. The defect in GM-CSF secretion suggests a hitherto unknown role of NOD2 in the pathogenesis of CD and is consistent with the hypothesis that impaired GM-CSF secretion in part constitutes a NOD2-dependent disease risk factor.",

author = "A Brosb{\o}l-Ravnborg and Hvas, {C L} and J Agnholt and Dahlerup, {J F} and I Vind and A Till and P Rosenstiel and P H{\"o}llsberg",

note = "Keywords: Acetylmuramyl-Alanyl-Isoglutamine; Case-Control Studies; Cell Proliferation; Cells, Cultured; Crohn Disease; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1beta; Ligands; Lipopolysaccharides; Nod2 Signaling Adaptor Protein; Polymorphism, Single Nucleotide; Signal Transduction; Statistics, Nonparametric; Toll-Like Receptors; Tumor Necrosis Factor-alpha",

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doi = "10.1111/j.1365-2249.2008.03850.x",

language = "English",

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pages = "487--95",

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T1 - Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways

AU - Brosbøl-Ravnborg, A

AU - Hvas, C L

AU - Agnholt, J

AU - Dahlerup, J F

AU - Vind, I

AU - Till, A

AU - Rosenstiel, P

AU - Höllsberg, P

N1 - Keywords: Acetylmuramyl-Alanyl-Isoglutamine; Case-Control Studies; Cell Proliferation; Cells, Cultured; Crohn Disease; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1beta; Ligands; Lipopolysaccharides; Nod2 Signaling Adaptor Protein; Polymorphism, Single Nucleotide; Signal Transduction; Statistics, Nonparametric; Toll-Like Receptors; Tumor Necrosis Factor-alpha

PY - 2008

Y1 - 2008

N2 - Pattern recognition receptors (PRRs) are an integral part of the innate immune system and govern the early control of foreign microorganisms. Single nucleotide polymorphisms (SNPs) in the intracellular pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD2, nucleotide oligomerization domain 2) are associated with Crohn's disease (CD). We investigated the impact of NOD2 polymorphisms on cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) in response to Toll-like receptor (TLR) and NOD2 ligands. Based on NOD2 SNP analyses, 41 CD patients and 12 healthy controls were studied. PBMCs were stimulated with NOD2 and TLR ligands. After 18 h culture supernatants were measured using multiplex assays for the presence of human cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 beta and tumour necrosis factor (TNF)-alpha. In CD patients, TLR-induced GM-CSF secretion was impaired by both NOD2-dependent and -independent mechanisms. Moreover, TNF-alpha production was induced by a TLR-2 ligand, but a down-regulatory function by the NOD2 ligand, muramyl dipeptide, was impaired significantly in CD patients. Intracellular TLR ligands had minimal effect on GM-CSF, TNF-alpha and IL-1beta secretion. CD patients with NOD2 mutations were able to secrete TNF-alpha, but not GM-CSF, upon stimulation with NOD2 and TLR-7 ligands. CD patients have impaired GM-CSF secretion via NOD2-dependent and -independent pathways and display an impaired NOD2-dependent down-regulation of TNF-alpha secretion. The defect in GM-CSF secretion suggests a hitherto unknown role of NOD2 in the pathogenesis of CD and is consistent with the hypothesis that impaired GM-CSF secretion in part constitutes a NOD2-dependent disease risk factor.

AB - Pattern recognition receptors (PRRs) are an integral part of the innate immune system and govern the early control of foreign microorganisms. Single nucleotide polymorphisms (SNPs) in the intracellular pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD2, nucleotide oligomerization domain 2) are associated with Crohn's disease (CD). We investigated the impact of NOD2 polymorphisms on cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) in response to Toll-like receptor (TLR) and NOD2 ligands. Based on NOD2 SNP analyses, 41 CD patients and 12 healthy controls were studied. PBMCs were stimulated with NOD2 and TLR ligands. After 18 h culture supernatants were measured using multiplex assays for the presence of human cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 beta and tumour necrosis factor (TNF)-alpha. In CD patients, TLR-induced GM-CSF secretion was impaired by both NOD2-dependent and -independent mechanisms. Moreover, TNF-alpha production was induced by a TLR-2 ligand, but a down-regulatory function by the NOD2 ligand, muramyl dipeptide, was impaired significantly in CD patients. Intracellular TLR ligands had minimal effect on GM-CSF, TNF-alpha and IL-1beta secretion. CD patients with NOD2 mutations were able to secrete TNF-alpha, but not GM-CSF, upon stimulation with NOD2 and TLR-7 ligands. CD patients have impaired GM-CSF secretion via NOD2-dependent and -independent pathways and display an impaired NOD2-dependent down-regulation of TNF-alpha secretion. The defect in GM-CSF secretion suggests a hitherto unknown role of NOD2 in the pathogenesis of CD and is consistent with the hypothesis that impaired GM-CSF secretion in part constitutes a NOD2-dependent disease risk factor.

U2 - 10.1111/j.1365-2249.2008.03850.x

DO - 10.1111/j.1365-2249.2008.03850.x

M3 - Journal article

C2 - 19094116

SN - 0009-9104

VL - 155

SP - 487

EP - 495

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

IS - 3

ER -

Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways

Abstract

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