Induction of HSP70 is dispensable for anti-inflammatory action of heat shock or NSAIDs in mast cells.
OBJECTIVE
It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, ibuprofen, and indomethacin, induce anti-inflammatory effects through inhibition of cyclooxygenase enzyme activity. However, it has also been established that a variety of their anti-inflammatory effects are independent of cyclooxygenase. In the search for alternative modes of action, it was found that NSAIDs share some cellular effects with heat shock treatment. This prompted us to investigate whether NSAIDs modulate production of proinflammatory cytokines by mast cells through the heat shock response.


METHODS
In mouse mast cells, derived from a culture of bone marrow cells of male BALB/cBy and null HSF-1(-/-) mice, responsiveness to heat shock and NSAIDs was monitored by measuring tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production and signaling pathways.


RESULTS
In bone marrow-derived mast cells (BMMC), we found that heat shock and a number of NSAIDs induced heat shock protein 70 (HSP70), which was closely paralleled with inhibition of IL-6 and TNF-alpha production. Surprisingly, in BMMC from HSF-1(-/-)mice, heat shock and selected NSAIDs were still able to suppress cytokine production in the absence of HSP70 induction.


CONCLUSIONS
In this article, we provide evidence that inhibition of release of proinflammatory cytokines by NSAIDs and heat shock may be attributed to inhibition of the inhibitory nuclear factor kappaB (NF-kappaB) kinase activity, extracellular signal-regulated kinases 1/2, and p38 pathways, resulting in decreased transcriptional activity of the NF-kappaB pathway.
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
Esmaeil
E
Mortaz
Frank A
FA
Redegeld
Nanne
N
Bloksma
Kathy
K
Dunsmore
Alvin
A
Denenberg
Hector R
HR
Wong
Frans P
FP
Nijkamp
Ferdi
F
Engels
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D015850:Interleukin-6; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases