Mechanistic insights into impaired dendritic cell function by rapamycin: inhibition of Jak2/Stat4 signaling pathway.
The suppressive effect of rapamycin on T cells has been extensively studied, but its influence on the function of APC is less clear. The data in this study demonstrated that immunostimulatory activity of B10 (H2(b)) dendritic cells (DC) exposed to rapamycin (rapa-DC) was markedly suppressed as evidenced by the induction of low proliferative responses and specific CTL activity in allogeneic (C3H, H2(k)) T cells. Administration of rapa-DC significantly prolonged survival of B10 cardiac allografts in C3H recipients. Treatment with rapamycin did not affect DC expression of MHC class II and costimulatory molecules or IL-12 production. Rapamycin did not inhibit DC NF-kappaB pathway, however, IL-12 signaling through Janus kinase 2/Stat4 activation was markedly suppressed. Indeed, Stat4(-/-) DC similarly displayed poor allostimulatory activity. The Stat4 downstream product, IFN-gamma, was also inhibited by rapamycin, but DC dysfunction could not solely be attributed to low IFN-gamma production as DC deficient in IFN-gamma still exhibited vigorous allostimulatory activity. Rapamycin did not affect DC IL-12R expression, but markedly suppressed IL-18Ralpha and beta expression, which may in turn down-regulate DC IL-12 autocrine activation.
Chiang
Po-Hui
PH
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
Wang
Lianfu
L
Bonham
C Andrew
CA
Liang
Xiaoyan
X
Fung
John J
JJ
Lu
Lina
L
Qian
Shiguang
S
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D053727:Interleukin-18 Receptor alpha Subunit; D053614:Janus Kinase 2; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053724:Receptors, Interleukin-18; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D004268:DNA-Binding Proteins; C508573:Il18r1 protein, mouse; D007166:Immunosuppressive Agents; D053727:Interleukin-18 Receptor alpha Subunit; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020123:Sirolimus