Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

• Published in: Biochemical pharmacology Vol. 80; no. 6; pp. 858 - 866
• Main Authors: Villalonga, Núria, David, Miren, Bielańska, Joanna, González, Teresa, Parra, David, Soler, Concepció, Comes, Núria, Valenzuela, Carmen, Felipe, Antonio
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.09.2010; Elsevier
• Subjects: Animals; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Bone Marrow Cells - cytology; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Cell Migration Inhibition - drug effects; Cell Migration Inhibition - immunology; Cells, Cultured; Diclofenac - pharmacology; Drug Delivery Systems - methods; Humans; Immunologic Factors - pharmacology; Immunomodulation; Inflammation; Jurkat Cells; Kv1.3 Potassium Channel - antagonists & inhibitors; Kv1.3 Potassium Channel - metabolism; Leukocytes; Leukocytes - drug effects; Leukocytes - immunology; Macrophages - cytology; Macrophages - immunology; Macrophages - pathology; Medical sciences; Mice; Non-steroidal anti-inflammatory drugs; Pharmacology. Drug treatments; Voltage-dependent K + channels; PMA; Immunomodulation; CTX; NSAID; PHA; Inflammation; BMDM; Kv; Leukocytes; COX; LPS; Non-steroidal anti-inflammatory drugs; T EM; MgTx; Voltage-dependent K + channels; Prostaglandin-endoperoxide synthase; Targeting; Enzyme; Leukocyte; Enzyme inhibitor; Ionic channel; Inorganic element; Voltage-dependent K; Diclofenac; Non steroidal antiinflammatory agent; Immunomodulator; Target; Arylacetic acid derivatives; Analgesic; channels; Antipyretic; Oxidoreductases; Potassium; Voltage-dependent K channels; immunomodulation; leukocytes; non-steroidal anti-inflammatory drugs; inflammation
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2010.05.012

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 Ca3.1). Because Kv1.3 is a very good target for autoimmune therapies, the effects of diclofenac on Kv1.3 are of high pharmacological relevance.