1. Academic Validation
  2. Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells

Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells

  • J Immunol. 2014 Dec 15;193(12):6135-43. doi: 10.4049/jimmunol.1303276.
André Said 1 Stephanie Bock 1 Trim Lajqi 1 Gerrit Müller 1 Günther Weindl 2
Affiliations

Affiliations

  • 1 Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany.
  • 2 Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany Guenther.Weindl@fu-berlin.de.
Abstract

Recent studies suggest a role for Autophagy in the secretion of IL-1 cytokines regulating the development of inflammatory diseases. The antimalarial drug and Autophagy/lysosome inhibitor chloroquine (CHQ) is considered as potential trigger of drug-induced or drug-aggravated psoriasis, in which Th17 cells sustain a persistent inflammation. In this study, we investigated the effect of CHQ on human monocyte-derived Langerhans-like cells (MoLC) and dendritic cells (MoDC) in response to IL-1β. The presence of CHQ reduced IL-12p70 release in both subsets, but surprisingly increased IL-6 production in MoDC and IL-23 in MoLC. Importantly, CHQ-treated MoLC promoted IL-17A secretion by CD4(+) T cells and elevated RORC mRNA levels, whereas IFN-γ release was reduced. The dysregulation of IL-12 family cytokines in MoLC and MoDC occurred at the transcriptional level. Similar effects were obtained with other late Autophagy inhibitors, whereas PI3K Inhibitor 3-methyladenine failed to increase IL-23 secretion. The modulated cytokine release was dependent on IL-1 cytokine activation and abrogated by a specific IL-1R antagonist. CHQ elevated expression of TNFR-associated factor 6, a common intermediate in IL-1R and TLR-dependent signaling. Accordingly, treatment with Pam3CSK4 and CHQ enhanced IL-23 release in MoLC and MoDC. CHQ inhibited autophagic flux, confirmed by increased LC3-II and p62 expression, and activated ERK, p38, and JNK MAPK, but only inhibition of p38 abrogated IL-23 release by MoLC. Thus, our findings indicate that CHQ modulates cytokine release in a p38-dependent manner, suggesting an essential role of Langerhans cells and dendritic cells in CHQ-provoked psoriasis, possibly by promoting Th17 immunity.

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