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

Núria Villalonga (1) , Miren David (2) , Joanna Bielańska (1) , Teresa González (2) , David Parra (3) , Concepció Soler (3) , Núria Comes (1) , Carmen Valenzuela (2) , Antonio Felipe (1)

1 Departament de Bioquímica i Biología Molecular
2 Instituto de Investigaciones Biomedicas
3 Facultat de Medicina

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-activated K channels (K3.1). Because Kv1.3 is a very good target for autoimmune therapies, the effects of diclofenac on Kv1.3 are of high pharmacological relevance.

Mots clés: Voltage-dependent K channels; inflammation; leukocytes; immunomodulation; non-steroidal anti-inflammatory drugs

Núria Villalonga, Miren David, Joanna Bielańska, Teresa González, David Parra, et al.. Immunomodulatory effects of Diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels. Biochemical Pharmacology, 2010, 80 (6), pp.858. ⟨10.1016/j.bcp.2010.05.012⟩. ⟨hal-00608940⟩