EL PAPEL DE LA MAP CINASA p38 EN LA REGULACIÓN DEL INFLAMASOMA EN MACRÓFAGOS SUSCEPTIBLES Y RESISTENTES A LA TOXINA LETAL DE BACILLUS ANTHRACIS

Abstract

The inflammasome is a multiprotein complex that controls activation of caspase-1 and proinflammatory cytokine production in response to different pathogens or intracellular components released in response to cell damage. The inflammation caused by the production of these cytokines is required to eliminate pathogens and repair damaged tissue. However, uncontrolled inflammation and abnormal production of interleukin-1β (IL- 1β) can lead to cell death. The activation of Nalp-1 inflammasome in response to Bacillus anthracis lethal toxin (LT) causes death of susceptible mice expressing Nalp1b1 allele. However, there is experimental evidence suggesting that in addition to activation of the inflammasome, LT needs to inactivate the p38 MAP kinase pathway to induce death in susceptible macrophages. However, if p38 MAP kinase regulates the activation of the inflammasome is still not known. Here we show that by negatively regulating the expression of NALP1, p38 MAP kinase negatively modulates the activity of caspase-1 and IL-1β secretion induced by LT of B. anthracis in susceptible macrophages. Interestingly, this happens only when p38 activation occurs via TLR2, but not via TLR4. However, the p38 MAP kinase activation via TLR2 or TLR4 does not prevent cell death induced macrophage inflammatory susceptible to LT. These data suggest that although p38 MAP kinase does not directly regulate the formation of the inflammasome and activation of Caspase-1 in response to the lethal toxin of B. anthracis, through negatively regulating NALP1 expression, p38 may prevent the formation of new inflammasomes and thus modulate the extent and/or intensity of the inflammatory response.