Abstract
Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-α (TNFα) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-α therapy with infliximab (IFX). However, approximately 30–40% of CD patients fail to respond to IFX with still unclear underlying mechanisms. This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. Under basal conditions, the mRNA for the cytokines TNFα, IL-23, IL-1β and the chemokines CXCL8/IL-8, CCL5/RANTES and CCL2/MCP-1 was up-regulated in monocytes from non-responders than responders. The expression of the same cytokines and CCL2/MCP-1 was higher in non-responders also upon LPS treatment. Moreover, higher secretion of TNFα, IL-1β, IFNγ and IL-2 proteins occurred in the supernatants of LPS-treated non-responders cells. Resistance to IFX in CD may result from a transcriptional dysregulation of circulating monocytes, leading to hyperactivation of pro-inflammatory pathways. Monocytes’ cytokine profile may thus represent a predictive marker of response to IFX. Monocytes were isolated from blood samples of 19 CD patients (11 responders, 8 non-responders) and incubated with or without LPS. Cytokine profiles were assessed by RT-qPCR and, in the supernatants, by ELISA assay.
Highlights
Crohn’s disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation
Lamina propria macrophages isolated from colonic biopsies of CD patients have been shown to spontaneously produce increased amounts of tumor necrosis factor (TNF), that correlate with the degree of tissue involvement and mucosal inflammation[3], demonstrating their central role in the perpetuation of inflammation
The expression of TNF-α, IL-1β, IL-23 appears higher in monocytes from non-responder patients than in responders, both under basal conditions and after priming with lipopolysaccharides from E. coli 0111:B4 (LPS)
Summary
Crohn’s disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-α (TNFα) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-α therapy with infliximab (IFX). This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. The expression of the same cytokines and CCL2/MCP-1 was higher in non-responders upon LPS treatment. Higher secretion of TNFα, IL-1β, IFNγ and IL-2 proteins occurred in the supernatants of LPS-treated non-responders cells. Monocytes were isolated from blood samples of 19 CD patients (11 responders, 8 nonresponders) and incubated with or without LPS. The hallmark of CD is a chronic inflammation promoted and sustained by hyperactivated effector immune cells through an increased production of proinflammatory cytokines, mainly tumor necrosis factor (TNF)[2]. Henri Mondor University Hospital, AP-HP, Université Paris Est-UPEC, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. 5These authors contributed : Federica Gaiani and Bianca Maria Rotoli. *email: Scientific Reports | (2020) 10:12238
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