title: Dentritic cell derived IL-18 production is inhibited by rapamycin and sanglifehrin A, but not cyclosporine A.
abstract: Interleukin-18 (IL-18), a product of dendritic cells (DC), is a pro-inflammatory cytokine involved in the pathogenesis of allograft rejection, vascular disease, arthritis and diabetes. Rapamycin (Rapa) is an immunosuppressant that inhibits T cell mTOR kinase activation. In contrast, Sanglifehrin A (SFA), is a cyclophilin-binding immunosuppressant that does not act on calcineurin phosphatases but appears to inhibit IL-2-dependent T cell proliferation. Rapa and SFA exert some immunosuppressive effects on DC by inhibiting IL-12 production, although their effects on DC have not been investigated as comprehensively as those on T cells. We aimed to determine the impact of these drugs on DC IL-18 synthesis in vivo and in vitro. We found in vivo that LPS-stimulated OX62(+) DC produced significantly more IL-18 mRNA, compared to OX62(+) DC depleted splenocytes (p<0.01) and non-LPS-stimulated OX62(+) DC (p<0.01). OX62(+)CD4(+) and OX62(+)CD4(-) cells produced similar amounts of IL-18 mRNA. Rapa and SFA, but not CsA, significantly inhibited IL-18 production from OX62(+) DC in vitro, in a dose-dependent manner (p<0.05). In vivo IL-18 production was also inhibited by Rapa and SFA in splenic OX62(+) DC (p<0.01). Finally, inhibition of IL-18 production by Rapa and SFA was independent of the FK506 or cyclophilin pathways, respectively. In conclusion, Rapa and SFA, but not CsA, block IL-18 production and this novel Rapa blockade effect on IL-18 may contribute to the ability of Rapa to inhibit chronic allograft nephropathy and restenosis.
authors.affiliation: Department of Pathology, University of Sydney, NSW 2006, Australia.
authors.forename: Hungta
authors.initials: H
authors.lastname: Ko
authors.forename: Brett D
authors.initials: BD
authors.lastname: Hambly
authors.forename: Josette M
authors.initials: JM
authors.lastname: Eris
authors.forename: Vicki
authors.initials: V
authors.lastname: Levidiotis
authors.forename: Kate
authors.initials: K
authors.lastname: Wyburn
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Chadban
authors.forename: Jian L
authors.initials: JL
authors.lastname: Yin
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D021983:Cyclophilins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007783:Lactones / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology; D016559:Tacrolimus / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D020382:Interleukin-18; D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A; D016572:Cyclosporine; D021983:Cyclophilins; D020123:Sirolimus; D016559:Tacrolimus