Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of interleukin-6-type cytokine signaling.
Activation of the transcription factor signal transducers and activators of transcription (STAT) 3 is a defining feature of the interleukin (IL)-6 family of cytokines, which include IL-6, leukemia inhibitory factor, and cardiotrophin-1. These cytokines, as well as STAT3 activation, have been shown to be protective for cardiac myocytes and necessary for ischemia preconditioning. However, the mechanisms that regulate IL-6-type cytokine signaling in cardiac myocytes are largely unexplored. We propose that the protective character of IL-6-type cytokine signaling in cardiac myocytes is determined principally by three mechanisms: redox status of the nonreceptor tyrosine kinase Janus kinase 1 (JAK) 1 that activates STAT3, phosphorylation of STAT3 within the transcriptional activation domain on serine 727, and STAT3-mediated induction of suppressor of cytokine signaling (SOCS) 3 that terminates IL-6-type cytokine signaling. Moreover, we hypothesize that hyperactivation of the JAK kinases, particularly JAK2, mismatched STAT3 serine-tyrosine phosphorylation or heightened STAT3 transcriptional activity, and SOCS3 induction may ultimately prove detrimental. Here we summarize recent evidence that supports this hypothesis, as well as additional possible mechanisms of JAK-STAT regulation. Understanding how IL-6-type cytokine signaling is regulated in cardiac myocytes has great significance for exploiting the therapeutic potential of these cytokines and the phenomenon of preconditioning.
Kurdi
Mazen
M
Division of Molecular Cardiology, Cardiovascular Research Institute, College of Medicine, The Texas A&M University System Health Science Center, College Station, TX 76504, USA.
Booz
George W
GW
D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D016503:Drug Delivery Systems; D006331:Heart Diseases / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000187:drug effects / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000187:drug effects / Q000378:metabolism
D002317:Cardiovascular Agents; D016207:Cytokines; D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507904:JAK1 protein, human; D053613:Janus Kinase 1