Sepsis, a leading cause of death in hospitalized patients, is characterized by lethal systemic inflammatory responses. JAK2 is an essential
tyrosine kinase modulating immune responses. However, the implications of JAK2 in infectious disorders remain undetermined. Here, we report that JAK2 inhibitors rescue animals from polymicrobial
sepsis in a clinically relevant time frame. JAK2 inhibition with
AG490 prevents
NF-kappaB activation, modulates macrophage activation, and restrains the production of inflammatory
cytokines. The inhibition of JAK2 blunted TNF production in both macrophages and splenocytes in a concentration-dependent manner. JAK2 inhibition specifically prevents LPS-induced STAT3
tyrosine phosphorylation without affecting
serine phosphorylation in macrophages. JAK2 inhibitor prevents the activation of the canonical p65RelA/p50NF-kappaB1 pathway but not the other
NF-kappaB proteins. In vivo, JAK2 inhibition restrains serum TNF levels by modulating TNF production in the lung and the spleen and protects mice from lethal
endotoxemia in a concentration-dependent manner.
AG490 also inhibits extracellular release of
HMGB1 from macrophages and prevents an increase in serum
HMGB1 levels during
sepsis. JAK2 inhibition started at 24 h after the onset of
sepsis rescued the mice from polymicrobial
sepsis. Our study is the first experimental evidence that JAK2 inhibitors may provide a pharmacological advantage for the treatment of
sepsis in a clinically relevant time frame.