Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells.
Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.
Bauer
K
K
Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Germany.
Kretzschmar
A K
AK
Cvijic
H
H
Blumert
C
C
Löffler
D
D
Brocke-Heidrich
K
K
Schiene-Fischer
C
C
Fischer
G
G
Sinz
A
A
Clevenger
C V
CV
Horn
F
F
D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D015850:Interleukin-6; D008164:Luminescent Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C081786:cyclophilin B; D008156:Luciferases; D021984:Cyclophilin A; D021983:Cyclophilins