The Jak/Stat Signaling Pathway Is Downregulated at Febrile Temperatures

Background: The Janus family of kinases (JAKs), Jak1, Jak2, Jak3, and Tyk2, constitute a subgroup of non-receptor protein tyrosine kinases. Upon cytokine binding, the receptor-associated kinases are activated and phosphorylate tyrosine residues in their cognate cytokine receptors. Their activities are controlled at several levels and include cellular concentration, auto-activation, and degradation. Principal Findings: Our findings show that elevated temperatures in the fever range irreversibly aggregate Jak2 and considerably reduce functional Jak2 protein levels. Jak2 synthesis remains unaltered. We observed that also the protein level of the signal transducer and activator of transcription, STAT5b, is transiently decreased at temperatures above 37 degrees C. Consequently, the signaling response, e. g. via the growth hormone receptor, is reduced. Conclusions/Significance: These findings predict that elevated body temperatures lower the responsiveness of cytokine receptors.