The Strong and the Weak - the Dual Role of JAK1 in Inflammatory Cytokine Production,

Abstract 3218

Inhibition of JAK1 is an emerging clinical concept that has promise for a variety of autoimmune diseases, myeloproliferative diseases and post-transplant immunosuppression, but similarly raises concerns regarding immunosuppressive side effects.

At the example of IL-12p70 production in human monocyte-derived dendritic cells we demonstrate that JAK1 has a dual role in differentially regulating effects of weak and strong activation stimuli. We have demonstrated recently that weak NF-kB-activating stimuli (e.g. CD40L or LPS) require complementary JAK1-targeting cytokines such as IFN-g to induce IL-12p70. This pathway involves RELA, CREL, JAK1 and/or JAK2, STAT1, IRF1 and IRF8 and is inhibited by RELB and TYK2 (Conzelmann et al. Biochem Pharm. 2010, 80(12):2074–86).

Here we provide evidence for an alternative IL-12 stimulating pathway depending on strong NF-kB activating stimuli (e.g. intact E. coli or LPS plus IL-1b). siRNA silencing demonstrated that this pathway is specifically inhibited by JAK1 and the transcription factor STAT3, but is not influenced by any of the other JAK/STAT family members. Both IL-12p35 and p40 mRNA expression is directly inhibited by STAT3. Furthermore, ChIP-assays revealed that STAT3 binds directly to a combined STAT/NF-kB site at the IL-12p35 promoter without altering access of RELA and CREL. Extending the cytokine panel we found that E.coli-induced IL-6 and TNF-a production is similarly inhibited by the JAK1/STAT3 pathway whereas IL-10 expression is not affected. The observed dual effects of JAK1 are clearly confirmed by the JAK1/2 inhibitor INCB018424 (Ruxolitinib) which enhances E.coli-induced cytokines whilst strongly inhibiting cytokine production stimulated by CD40L/IFN-g.

In summary, our study suggests that blockade of JAK1 specifically inhibits pro-inflammatory effects of weak, IFN-g dependent, NF-kB activating stimuli while enhancing inflammatory cytokine expression induced by strong activation stimuli. Inhibition of JAK1/2 by INCB018424 (Ruxolitinib) would therefore represent a novel immunosuppressive approach that may spare the immune defence against invading pathogens.