JNK activation limits dendritic cell maturation in response to reactive oxygen species by the induction of apoptosis

Abstract

Dendritic cells (DC) sense infection in their local microenvironment and respond appropriately in order to induce T cell immunity. This response is mediated in part via the mitogen-activated protein kinase (MAPK) pathways. Hydrogen peroxide is present frequently in the inflammatory DC milieu and is known to activate MAPK. Therefore this study examines the role of hydrogen peroxide, both alone and in combination with lipopolysaccharide (LPS), in the regulation of activation of two key MAPK, p38 and JNK, regulation of phenotype, and regulation of apoptosis in human monocyte-derived DC. At low concentrations, hydrogen peroxide activates p38, but does not alter DC phenotype. At higher concentrations, hydrogen peroxide activates both p38 and JNK. Activation of JNK, which is associated with inhibition of tyrosine phosphatases in DC, is linked to the induction of DC apoptosis. An upstream JNK inhibitor (CEP11004) and a competitive JNK inhibitor (SP600125) both partially protected the DC from the proapoptotic effects of hydrogen peroxide. Unexpectedly, hydrogen peroxide and LPS synergize in inducing JNK activation and DC apoptosis. JNK-mediated apoptosis may limit damaging immune responses against neoepitopes generated by modification of self-antigens by reactive oxygen species present at sites of inflammation.