Infliximab therapy increases the frequency of circulating CD16+ monocytes and modifies macrophage cytokine response to bacterial infection

Abstract

SummaryCrohn's disease (CD) has been correlated with altered macrophage response to microorganisms. Considering the efficacy of infliximab treatment on CD remission, we investigated infliximab effects on circulating monocyte subsets and on macrophage cytokine response to bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, treated or not with infliximab. Macrophages were infected with Escherichia coli, Enterococcus faecalis, Mycobacterium avium subsp. paratuberculosis (MAP) or M. avium subsp avium, and cytokine levels [tumour necrosis factor (TNF) and interleukin (IL)-10] were evaluated at different time-points. To evaluate infliximab-dependent effects on monocyte subsets, we studied CD14 and CD16 expression by peripheral blood monocytes before and after different infliximab administrations. We also investigated TNF secretion by macrophages obtained from CD16 + and CD16 − monocytes and the frequency of TNF + cells among CD16 + and CD16 − monocyte-derived macrophages from CD patients. Infliximab treatment resulted in elevated TNF and IL-10 macrophage response to bacteria. An infliximab-dependent increase in the frequency of circulating CD16 + monocytes (particularly the CD14 ++ CD16 + subset) was also observed (before infliximab: 4·65 ± 0·58%; after three administrations: 10·68 ± 2·23%). In response to MAP infection, macrophages obtained from CD16 + monocytes were higher TNF producers and CD16 + macrophages from infliximab-treated CD patients showed increased frequency of TNF + cells. In conclusion, infliximab treatment increased the TNF production of CD macrophages in response to bacteria, which seemed to depend upon enrichment of CD16 + circulating monocytes, particularly of the CD14 ++ CD16 + subset. Infliximab treatment of CD patients also resulted in increased macrophage IL-10 production in response to bacteria, suggesting an infliximab-induced shift to M2 macrophages.

Crohn’s Disease Biologic Therapies Advances: A current review

“…The mechanism of action is not clear but there are evidence points, such as induction of apoptosis of immune cells, neutralization of soluble and transmembrane TNF-α, alteration of cytokine secretion and induction of immunoregulatory macrophages. According to current data, the most important pathways induced by this drug are not directly related to TNF-α neutralization as can be observed in Table 1 and 2 [9].…”

“…This is done by elimination of microbial agents, production cytokines and presentation antigen to other cells of the adaptive IS. These phagocytic cells, mainly the intermediate subset of macrophages, has shown low activity in the production of inflammatory cytokines in health intestinal in compared with CD patients [9].…”

“…al showed that macrophages had an enhances TNF bacterial-stimulation in response to infection for bacteria's in CD patients submitted an IFX therapy compared with CD patients without IFX and even less in health controls, in isolate mononuclear cells of Peripheral Blood (PB) [9]. It was also evident that CD16 + monocytes were more frequent in the PB of CD patients (6.10% ± 0.71%) than in HC (4.01% ± 0.98%).…”

“…It has been shown that IS exacerbated response leading to the imbalance between the proinflammatory and antiinflammatory cytokines produced by the mucosa in response to inflammation [5,9,10]. This lead to a disproportionate activation of T helper (Th)1 cells and an overproduction of Interleukin (IL).…”

“…One of the most potent proinflammatory mediators is the TNF-α contributing to the destruction of the intestinal mucosa. This has contributed to chronically activated IS leading to chronic inflammation [9].…”