Intracellular chloride acts as a second Messenger for CFTR modulating IL-1β expression

MARÍA MACARENA MASSIP COPIZ; JUAN M. FIGUEROA; ANGEL GABRIEL VALDIVIESO; ANDREA V. DUGOUR; MARIÁNGELES CLAUZURE; CONSUELO MORI; TOMÁS A. SANTA COLOMA

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2016

The CFTR gene is responsible for Cystic Fibrosis (CF). TheCFTR protein is a cAMP-regulated chloride channel. Several cellularfunctions are altered in CF cells. However, it is not clear howthe CFTR failure induces those alterations. By using differentialdisplay, we have found previously several CFTR-dependent genes,including c-Src, MUC1, MTND4 and CISD1. We also reportedthe existence of chloride-dependent genes, such as GLRX5 andRPS27. Here, using nigericin and tributyltin to clamp the pH andthe intracellular chloride concentration [Cl-]i of IB3-1 epithelialcells, we show that IL-1β is also a Cl-dependent gene that canbe modulated by changing the intracellular chloride concentration,in a biphasic way. The IL-1β secretion also showed a similar patternof response to changes in [Cl-]i. The mechanism involves anIL-1β autocrine effect, since in the presence of the IL-1β receptorantagonist IL1RN and anti-IL-1β blocking antibody, Cl- effectsdisappeared. Similar effects were obtained with the JNK inhibitor,c-Src inhibitor and the IKK inhibitor, suggesting that JNK, c-Src andNF-kB are important mediators of the [Cl-]i signaling. In conclusion,the Cl- anion act as a second messenger for CFTR, modulating theexpression and secretion of IL-1β, through an autocrine IL-1β loopthat involves IKK, c-Src and JNK kinases. This work was supportedby National Agency for the Promotion of Science and Technology(ANPCYT) [grant numbers PICT 2007-00628 and PICT 2012-1278]to TASC; National Scientific and Technical Research Council ofArgentina (CONICET) [grant PIP 112200801025512009-2011 andPIP 11220110100685 2012-2014] to TASC; Pontifical CatholicUniversity of Argentina (UCA) to TASC and a grant from PabloCassará Foundation (AVD and JMF); and research fellowshipsfrom CONICET (to MMMC, CM and MC).