Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels.
Kv1.3 plays a crucial role in the activation and proliferation of T-lymphocytes and macrophages. While Kv1.3 is responsible for the voltage-dependent potassium current in T-cells, in macrophages this K(+) current is generated by the association of Kv1.3 and Kv1.5. Patients with autoimmune diseases show a high number of effector memory T cells that are characterized by a high expression of Kv1.3 and Kv1.3 antagonists ameliorate autoimmune disorders in vivo. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used in patients who suffer from painful autoimmune diseases such as rheumatoid arthritis. In this study, we show that diclofenac impairs immune response via a mechanism that involves Kv1.3. While diclofenac inhibited Kv1.3 expression in activated macrophages and T-lymphocytes, Kv1.5 remained unaffected. Diclofenac also decreased iNOS levels in Raw 264.7 cells, impairing their activation in response to lipopolysaccharide (LPS). LPS-induced macrophage migration and IL-2 production in stimulated Jurkat T-cells were also blocked by pharmacological doses of diclofenac. These effects were mimicked by Margatoxin, a specific Kv1.3 inhibitor, and Charybdotoxin, which blocks both Kv1.3 and Ca(2+)-activated K(+) channels (K(Ca)3.1). Because Kv1.3 is a very good target for autoimmune therapies, the effects of diclofenac on Kv1.3 are of high pharmacological relevance.
Villalonga
Núria
N
Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona. Avda Diagonal 645, E-08028 Barcelona, Spain. nvillalonga@gmail.com
David
Miren
M
Bielańska
Joanna
J
González
Teresa
T
Parra
David
D
Soler
Concepció
C
Comes
Núria
N
Valenzuela
Carmen
C
Felipe
Antonio
A
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004008:Diclofenac / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051379:Mice
D007155:Immunologic Factors; D051664:Kv1.3 Potassium Channel; D004008:Diclofenac