PMID- 18662782
OWN - NLM
STAT- MEDLINE
DCOM- 20090309
LR  - 20211203
IS  - 0966-3274 (Print)
IS  - 0966-3274 (Linking)
VI  - 20
IP  - 1-2
DP  - 2008 Nov
TI  - Dentritic cell derived IL-18 production is inhibited by rapamycin and 
      sanglifehrin A, but not cyclosporine A.
PG  - 99-105
LID - 10.1016/j.trim.2008.07.001 [doi]
AB  - 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.
FAU - Ko, Hungta
AU  - Ko H
AD  - Department of Pathology, University of Sydney, NSW 2006, Australia.
FAU - Hambly, Brett D
AU  - Hambly BD
FAU - Eris, Josette M
AU  - Eris JM
FAU - Levidiotis, Vicki
AU  - Levidiotis V
FAU - Wyburn, Kate
AU  - Wyburn K
FAU - Wu, Huiling
AU  - Wu H
FAU - Chadban, Steve J
AU  - Chadban SJ
FAU - Yin, Jian L
AU  - Yin JL
LA  - eng
PT  - Journal Article
DEP - 20080726
PL  - Netherlands
TA  - Transpl Immunol
JT  - Transplant immunology
JID - 9309923
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-18)
RN  - 0 (Lactones)
RN  - 0 (Spiro Compounds)
RN  - 0 (sanglifehrin A)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 5.2.1.- (Cyclophilins)
RN  - W36ZG6FT64 (Sirolimus)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/drug effects/immunology
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cyclophilins/metabolism
MH  - Cyclosporine/*pharmacology
MH  - Dendritic Cells/*drug effects/immunology
MH  - *Immunosuppression Therapy
MH  - Immunosuppressive Agents/*pharmacology
MH  - Interleukin-18/*antagonists & inhibitors/biosynthesis
MH  - Lactones/pharmacology
MH  - Rats
MH  - Rats, Inbred Lew
MH  - Sirolimus/*pharmacology
MH  - Spiro Compounds/pharmacology
MH  - Tacrolimus/metabolism
EDAT- 2008/07/30 09:00
MHDA- 2009/03/10 09:00
CRDT- 2008/07/30 09:00
PHST- 2008/04/10 00:00 [received]
PHST- 2008/06/23 00:00 [revised]
PHST- 2008/07/03 00:00 [accepted]
PHST- 2008/07/30 09:00 [pubmed]
PHST- 2009/03/10 09:00 [medline]
PHST- 2008/07/30 09:00 [entrez]
AID - S0966-3274(08)00052-X [pii]
AID - 10.1016/j.trim.2008.07.001 [doi]
PST - ppublish
SO  - Transpl Immunol. 2008 Nov;20(1-2):99-105. doi: 10.1016/j.trim.2008.07.001. Epub 
      2008 Jul 26.