Nickel Sulfate Promotes IL-17A Producing CD4+ T Cells by an IL-23-Dependent Mechanism Regulated by TLR4 and Jak-STAT Pathways

Abstract

Allergic contact dermatitis, caused by nickel, is a delayed-type hypersensitivity reaction, and 14.5% of the general population may be affected in Europe. Among a wide range of cytokines, the IL-12 family has unique structural and immunological characteristics. Whereas IL-12p70 promotes T helper (Th) 1 cell polarization, IL-23 promotes Th17 cell development and both have been isolated from nickel-allergic patients. In this work, we were interested in understanding the mechanism behind nickel-induced Th17 cell development. We showed that nickel induced an early production of IL-23 in human monocyte-derived dendritic cells along with an increase in the expression of il-23p19 and il-12p40 mRNA. However, the production of a significant level of IL-12p70 required an additional signal such as IFN-γ. Moreover, nickel-treated monocyte-derived dendritic cells induced an increase in the percentage of IL-17A CD4 T cells, an effect reduced by IL-23 neutralization. We then investigated the molecular mechanism of IL-23 production. Our results showed that toll-like receptor 4, p38 mitogen-activated protein kinase, and NF-κB were involved in IL-23 production induced by nickel. However, Jak-signal transducer and activator of transcription activation seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. These results indicate that nickel-induced Th17 cell development is dependent on the production of IL-23 by human monocyte-derived dendritic cells via toll-like receptor 4, p38 mitogen-activated protein kinase, NF-κB, and Jak-signal transducer and activator of transcription pathways.

The effect of anti-IL-17 treatment on the reaction to a nickel patch test in patients with allergic contact dermatitis

“…Bechara et al . found that exposure to nickel in human monocyte‐derived dendritic cells leads to an upregulation of IL‐23, and this cytokine has an important role in the development of Th17 cells and the production of IL‐17A, which is in line with the results of a previous study .…”

Non–heat inactivated autologous serum increases accuracy of in vitro CFSE lymphocyte proliferation test (LPT) for nickel

“…This illustrates another strength of this test as there is often a significant delay between exposure and diagnostic work‐up. Our study confirms previous findings by us and others that CD4 + cells are the dominant proliferating population and thereby also verifies a cell‐mediated hypersensitivity reaction 7,31‐33 . Furthermore, by discriminating CD4 + from CD8 + cells, higher SI’s and better diagnostic values could be found.…”

Growth Hormone Aggregates Activation of Human Dendritic Cells Is Controlled by Rac1 and PI3 Kinase Signaling Pathways

“…12 Previous reports also demonstrated activation of MAPKs and NF-kB subunit p65 in moDC in response to danger signals such as lipopolysaccharide and contact sensitizers, such as nickel. 14,16,19 We were then interested in the upstream signaling pathways that participated in DC response to hGH aggregates. Both Rac1 and PI3K are highly involved in actin remodeling observed in phagocytosis, the internalization mechanism of large insoluble particles by innate immune cells such as macrophages, neutrophils, and dendritic cells.…”

“…Inhibitors concentrations and treatment timelines were optimized to avoid cellular toxicity, according to previous studies. 16 Results showed that cxcl10 expression was decreased when moDCs were pretreated with these inhibitors, suggesting that hGH aggregates modulate cxcl10 expression via NF-kB, ERK, JNK, and p38 MAPK signaling pathways (Fig. 3a).…”