Thymic atrophy, due to the depletion of CD4(+) CD8(+) thymocytes, is observed during infections with numerous pathogens. Several mechanisms, such as glucocorticoids and inflammatory cytokines, are known to be involved in this process; however, the roles of intracellular signaling molecules have not been investigated. In this study, the functional role of c-Jun NH2 -terminal kinase (JNK) during infection-induced thymic atrophy was addressed. The levels of phosphorylated JNK in immature CD4(+) CD8(+) thymocytes from C57BL/6 (Nramp-deficient) and 129/SvJ (Nramp-sufficient) mice were increased upon oral infection of mice with Salmonella enterica serovar Typhimurium (S. typhimurium). Furthermore, inhibition of JNK signaling, but not ERK or p38 MAPK, prevented the in vitro death of infected thymocytes. Importantly, the in vivo inhibition of JNK signaling with SP600125 protected C57BL/6 CD4(+) CD8(+) thymocytes from depletion via multiple mechanisms as follows: lower intracellular ROS, inflammatory cytokines, Bax and caspase 3 activity, increase in Bcl-xL amounts, and prevention of the loss in mitochondrial membrane potential. Notably, thymic architecture was preserved in infected mice treated with SP600125. Overall, this study identifies a novel role for JNK as a crucial regulator of the death of CD4(+) CD8(+) thymocytes during S. typhimurium infection.
Keywords: Cell death; Glucocorticoids; IFN-γ; JNK activation; Thymic atrophy.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.