RESUMO
The Kv1.3 channel has been widely demonstrated to play crucial roles in the activation and proliferation of T cells, which suggests that selective blockers could serve as potential therapeutics for autoimmune diseases mediated by T cells. We previously described that the toxin mimic FS48 from salivary gland of Xenopsylla cheopis downregulates the secretion of proinflammatory factors by Raw 264.7 cells by blocking the Kv1.3 channel and the subsequent inactivation of the proinflammatory MAPK/NF-κB pathways. However, the effects of FS48 on human T cells and autoimmune diseases are unclear. Here, we described its immunomodulatory effects on human T cells derived from suppression of Kv1.3 channel. Kv1.3 currents in Jurkat T cells were recorded by whole-cell patch-clamp, and Ca2+ influx, cell proliferation, and TNF-α and IL-2 secretion were measured using Fluo-4, CCK-8, and ELISA assays, respectively. The in vivo immunosuppressive activity of FS48 was evaluated with a rat DTH model. We found that FS48 reduced Kv1.3 currents in Jurkat T cells in a concentration-dependent manner with an IC50 value of about 1.42 µM. FS48 also significantly suppressed Kv1.3 protein expression, Ca2+ influx, MAPK/NF-κB/NFATc1 pathway activation, and TNF-α and IL-2 production in activated Jurkat T cells. Finally, we show that FS48 relieved the DTH response in rats. We therefore conclude that FS48 can block the Kv1.3 channel and inhibit human T cell activation, which most likely contributes to its immunomodulatory actions and highlights the great potential of this evolutionary-guided peptide as a drug template in future studies.
Assuntos
Doenças Autoimunes , Canal de Potássio Kv1.3 , Venenos de Escorpião , Linfócitos T , Xenopsylla , Adjuvantes Imunológicos/farmacologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Humanos , Fatores Imunológicos/farmacologia , Interleucina-2/metabolismo , Canal de Potássio Kv1.3/imunologia , Ativação Linfocitária/efeitos dos fármacos , NF-kappa B/metabolismo , Bloqueadores dos Canais de Potássio/imunologia , Ratos , Glândulas Salivares/química , Venenos de Escorpião/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Xenopsylla/químicaRESUMO
The inflammatory response plays important roles in acne vulgaris and pain pathogenesis. In previous study, Esc-1GN with anti-inflammatory, antimicrobial, and lipopolysacchride (LPS) binding activity was identified from the skin of the frog Hylarana guentheri. Here, we report its therapeutic potentials for acne vulgaris and inflammatory pain. Esc-1GN destroyed the cell membrane of Propionibacteria acnes in the membrane permeability assays. In addition, bacterial agglutination test suggested that Esc-1GN triggered the agglutination of P. acnes, which was affected by LPS and Ca2+ . Meanwhile, in vivo anti-P. acnes and anti-inflammatory effects of Esc-1GN were confirmed by reducing the counts of P. acnes in mice ear, relieving P. acnes-induced mice ear swelling, decreasing mRNA expression and the production of pro-inflammatory cytokines, and attenuating the infiltration of inflammatory cells. Moreover, Esc-1GN also displayed antinociceptive effect in mice induced by acetic acid and formalin. Therefore, Esc-1GN is a promising candidate drug for treatment of acne vulgaris and inflammatory pain.