JAK2 Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages

A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 (JAK2) gene (JAK2 ) has been detected in myeloid cells of some individuals with higher levels of proinflammatory cytokine production such as interleukin (IL)-6. However, the mechanisms by which JAK2 mutation mediating those cytokines remain unclear. We, therefore, established JAK2 -expressing murine macrophages (JAK2 macrophages) and found that the levels of p-STAT3 were markedly elevated in JAK2 macrophages in association with an increase in IL-6 production. However, inhibition of STAT3 by C188-9 significantly decreased the production of IL-6. Furthermore, the JAK2 mutation endowed macrophages with an elevated glycolytic phenotype in parallel with aberrant expression of PKM1. Interestingly, silencing of PKM1 inactivated STAT3 in parallel with reduced IL-6 production. In contrast, ectopic expression of PKM1 elevated IL-6 production via STAT3 activation. Importantly, the JAK2 mutation contributed to PKM1 protein stabilization via blockade of lysosomal-dependent degradation via chaperone-mediated autophagy (CMA), indicating that the JAK2 mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.