Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties.
Hydroxychloroquine (HCQ), a lysosomotropic amine, is an immunosuppressive agent presently being evaluated in bone marrow transplant patients to treat graft-versus-host disease. While its immunosuppressive properties have been attributed primarily to its ability to interfere with antigen processing, recent reports demonstrate HCQ also blocks T-cell activation in vitro. To more precisely define the T-cell inhibitory effects of HCQ, the authors evaluated T-cell antigen receptor (TCR) signaling events in a T-cell line pretreated with HCQ. In a concentration-dependent manner, HCQ inhibited anti-TCR-induced up-regulation of CD69 expression, a distal TCR signaling event. Proximal TCR signals, including inductive protein tyrosine phosphorylation, tyrosine phosphorylation of phospholipase C gamma1, and total inositol phosphate production, were unaffected by HCQ. Strikingly, anti-TCR-crosslinking-induced calcium mobilization was significantly inhibited by HCQ, particularly at the highest concentrations tested (100 micromol/L) in both T-cell lines and primary T cells. HCQ, in a dose-dependent fashion, also reduced a B-cell antigen receptor calcium signal, indicating this effect may be a general property of HCQ. Inhibition of the calcium signal correlated directly with a reduction in the size of thapsigargin-sensitive intracellular calcium stores in HCQ-treated cells. Together, these findings suggest that disruption of TCR-crosslinking-dependent calcium signaling provides an additional mechanism to explain the immunomodulatory properties of HCQ.
Goldman
F D
FD
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA. frederick-goldman@uiowa.edu
Gilman
A L
AL
Hollenback
C
C
Kato
R M
RM
Premack
B A
BA
Rawlings
D J
DJ
D015703:Antigens, CD / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D002118:Calcium / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D019169:Jurkat Cells; D007700:Kinetics; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D007295:Inositol Phosphates; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D013755:Tetradecanoylphorbol Acetate; D000099192:CD69 Antigens