PMID- 10203577
OWN - NLM
STAT- MEDLINE
DCOM- 19990611
LR  - 20181113
IS  - 1076-1551 (Print)
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Linking)
VI  - 5
IP  - 2
DP  - 1999 Feb
TI  - Suppressive effects of anti-inflammatory agents on human endothelial cell 
      activation and induction of heat shock proteins.
PG  - 117-28
AB  - BACKGROUND: Studies from our laboratory have shown that the earliest stages of 
      atherosclerosis may be mediated by an autoimmune reaction against heat shock 
      protein 60 (Hsp60). The interactions of Hsp60-specific T cells with arterial 
      endothelial cells (EC) require expression of both Hsp60 and certain adhesion 
      molecules shown to be induced simultaneously in EC by mechanical and other types 
      of stress. Recently, it was shown that suppression of T cell-mediated immune 
      responses by cyclosporin A (CyA) enhanced atherosclerotic lesion formation in 
      mice. In contrast, aspirin was found to lower the risk of myocardial infarction 
      in men. These conflicting observations may be due to different effects of 
      anti-inflammatory agents on adhesion molecule and Hsp expression in EC, 
      respectively. MATERIAL AND METHODS: In the present study, we analyzed the effects 
      of CyA, aspirin, and indomethacin on T cell proliferation using a proliferation 
      assay. To explore the expression of adhesion molecules, monocyte chemoattractant 
      protein-1 (MCP-1), and Hsp60 in human umbilical vein endothelial cells (HUVECs), 
      Northern blot analyses were used. To examine the activation status of the 
      transcription factors nuclear factor kappaB (NF-kappaB) and heat shock factor-1 
      (HSF-1), electrophoretic mobility shift assays were performed. RESULTS: With the 
      exception of indomethacin, the used immunosuppressive and anti-inflammatory 
      agents significantly inhibited T cell proliferation in response to influenza 
      virus antigen in a dose-dependent manner. Interestingly, CyA and indomethacin did 
      not suppress tumor necrosis factor-alpha (TNF-alpha)-induced adhesion molecule 
      expression on HUVECs, whereas aspirin had an inhibitory effect. These 
      observations correlated with the modulation of NF-kappaB activity in EC. All 
      agents tested induced expression of Hsp60 6 hr after application. In addition, 
      aspirin and indomethacin, but not CyA, induced Hsp70 expression in HUVECs that 
      correlated with induction of HSF-1 activity. CONCLUSION: Our results show that 
      the tested agents (except indomethacin) are inhibitors of the T cell-mediated 
      immune response, as expected, that aspirin is an effective suppressor of adhesion 
      molecule expression, and that all three agents can induce Hsp60 in HUVECs. These 
      data provide the molecular basis for the notion that (1) part of the 
      anti-atherogenic effect of aspirin may be due to the prevention of the adhesion 
      of sensitized T cells to stressed EC; (2) that part of the 
      atherosclerosis-promoting effect of CyA may be due to its potential as an inducer 
      of Hsp60 expression and its inability to down-regulate adhesion molecule 
      expression on EC; and (3) that down-regulation of MCP-1 expression by aspirin may 
      result in decreased recruitment of monocytes into the arterial intima beneath 
      stressed EC.
FAU - Amberger, A
AU  - Amberger A
AD  - Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, 
      Austria.
FAU - Hala, M
AU  - Hala M
FAU - Saurwein-Teissl, M
AU  - Saurwein-Teissl M
FAU - Metzler, B
AU  - Metzler B
FAU - Grubeck-Loebenstein, B
AU  - Grubeck-Loebenstein B
FAU - Xu, Q
AU  - Xu Q
FAU - Wick, G
AU  - Wick G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Chaperonin 60)
RN  - 0 (Chemokine CCL2)
RN  - 0 (E-Selectin)
RN  - 0 (HSP70 Heat-Shock Proteins)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (NF-kappa B)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - R16CO5Y76E (Aspirin)
RN  - XXE1CET956 (Indomethacin)
SB  - IM
MH  - Adult
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Aspirin/pharmacology
MH  - Cell Division/drug effects
MH  - Cells, Cultured/drug effects/metabolism
MH  - Chaperonin 60/drug effects/metabolism
MH  - Chemokine CCL2/metabolism
MH  - Cyclosporine/pharmacology
MH  - E-Selectin/drug effects/metabolism
MH  - Endothelium, Vascular/cytology/*drug effects/metabolism
MH  - Female
MH  - HSP70 Heat-Shock Proteins/drug effects/metabolism
MH  - Heat-Shock Proteins/*drug effects/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Indomethacin/pharmacology
MH  - Intercellular Adhesion Molecule-1/drug effects/metabolism
MH  - Lymphocytes/drug effects/metabolism
MH  - Male
MH  - NF-kappa B/drug effects/genetics/metabolism
MH  - Transcription Factors/drug effects/genetics/metabolism
MH  - Vascular Cell Adhesion Molecule-1/drug effects/metabolism
PMC - PMC2230414
EDAT- 1999/04/16 00:00
MHDA- 1999/04/16 00:01
PMCR- 1999/02/01
CRDT- 1999/04/16 00:00
PHST- 1999/04/16 00:00 [pubmed]
PHST- 1999/04/16 00:01 [medline]
PHST- 1999/04/16 00:00 [entrez]
PHST- 1999/02/01 00:00 [pmc-release]
AID - 0092 [pii]
PST - ppublish
SO  - Mol Med. 1999 Feb;5(2):117-28.