Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells.
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.
Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany.
André
A
Said
Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany.
Stephanie
S
Bock
Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany.
Trim
T
Lajqi
Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany.
Gerrit
G
Müller
Pharmakologie und Toxikologie, Institut für Pharmazie, Freie Universität Berlin, D-14195 Berlin, Germany Guenther.Weindl@fu-berlin.de.
Günther
http://orcid.org/0000-0002-4493-7597
G
Weindl
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002738:Chloroquine / Q000494:pharmacology*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000096:biosynthesis*; D007801:Langerhans Cells / Q000166:cytology / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D017472:Receptors, Interleukin-1; D018125:Receptors, Transforming Growth Factor beta; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6; D018664:Interleukin-12; D002738:Chloroquine; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I