Altered pattern of tumor necrosis factor-alpha production in peripheral blood monocytes from Crohn's disease

Abstract

AIMTo evaluate the inflammatory state in Crohn’s disease (CD) patients and correlate it with genetic background and microbial spreading.METHODSBy means of flow cytometry, production of tumor necrosis factor-alpha (TNF-α) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis (UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants (R702W, G908R and L1007Pfs*2) and basal production of TNF-α was correlated to NOD2 genotype. Also, production of TNF-α was correlated to plasmatic levels of LPS Binding Protein (LBP), soluble (s) CD14 and to the activity state of the disease.RESULTSThe patients with CD were characterized by a significantly higher monocyte basal expression of TNF-α compared with healthy subjects and UC patients, and after stimulation with Pam3CSK4 (ligand of TLR2/1) and MDP-L18 (ligand of NOD2) this difference was maintained, while other microbial stimuli (LPS, ligand of TLR4 and PolyI:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF-α between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-α production did not show a clear correlation with either LBP or sCD14 levels in plasma. Moreover, no clear correlation was seen between TNF-α production and activity indices in either CD or UC.CONCLUSIONPeripheral monocytes from CD express higher basal and stimulated TNF-α than controls, regardless of NOD2 genotype and without a clear correlation with disease activity.

Oral lymphangiectasia and gastrointestinal Crohn disease

“…[33][34][35] It was shown that peripheral monocytes from patients with CD have higher basal production of TNF-α regardless of NOD2 genotype and without a clear correlation with disease activity. 36 There are also reported cases of granulomatous vulvitis with occasional lymphangiectasia secondary to CD. [37][38][39] In this case, emphasis should be given to the cooccurrence of the ectatic lymphatic vessels and granulomatous inflammation that is notably associated with CD.…”

“…Lymphostasis in CD may lead to poor clearance of antigen, localized immune dysfunction, and persistent inflammation which may contribute to stimulation of macrophages to proliferate and aggregate in the lymphatic vessels, where tumor necrosis factor (TNF) alpha may play a crucial role in intralymphatic “histiocytic” immunopathogenesis 33‐35 . It was shown that peripheral monocytes from patients with CD have higher basal production of TNF‐α regardless of NOD2 genotype and without a clear correlation with disease activity 36 . There are also reported cases of granulomatous vulvitis with occasional lymphangiectasia secondary to CD 37‐39 .…”

A Versatile Intestine‐on‐Chip System for Deciphering the Immunopathogenesis of Inflammatory Bowel Disease

“…This finding is in agreement with clinical studies suggesting that MN‐derived TNF‐α and IL‐1β are high‐level drivers of intestinal inflammation in IBD. [ 110,111 ] We showed that iDCs properly matured, underwent activation, and exhibited apical antigen sampling functions, as inflammatory stimuli induced higher levels of GM‐CSF in IEB model‐iDC co‐cultures (Figure 6b‐iii). Such proper maturation and activation of iDCs has been shown to initiate subsequent T cell‐driven inflammatory responses in the onset of IBD.…”

Association between genotypes of rs34436714 of NLRP12 and serum tumor necrosis factor-alpha in inflammatory bowel disease

“…It has been shown that circulating monocytes of patients with CD produce more TNFα than healthy volunteers or patients with UC. [11] Although it is anticipated that greater production of TNFα may be associated with the behavior of CD and refractoriness to treatment, such data are not published. To this end, only indirect evidence is available.…”