Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling.
Heat shock protein (HSP) 27 has long been known to be a component of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. p38 MAPK has important functions in the inflammatory response, but the role of HSP27 in inflammation has remained unknown. We have used small interfering RNAs to suppress HSP27 expression in HeLa cells and fibroblasts and found that it is required for pro-inflammatory cell signaling and the expression of pro-inflammatory genes. HSP27 is needed for the activation by interleukin (IL)-1 of TAK1 and downstream signaling by p38 MAPK, JNK, and their activators (MKK-3, -4, -6, -7) and IKKbeta. IL-1-induced ERK activation appears to be independent of HSP27. HSP27 is required for both IL-1 and TNF-induced signaling pathways for which the most upstream common signaling protein is TAK1. HSP27 is also required for IL-1-induced expression of the pro-inflammatory mediators, cyclooxygenase-2, IL-6, and IL-8. HSP27 functions to drive cyclooxygenase-2 and IL-6 expression by augmenting the activation of the kinase downstream of p38 MAPK, MK2, resulting in stabilization of cyclooxygenase-2 and IL-6 mRNAs. The mechanism may not occur in cells of myeloid lineage because HSP27 protein was undetectable in human monocytes and murine macrophages.
Alford
Kate A
KA
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom.
Glennie
Sarah
S
Turrell
Bryony R
BR
Rawlinson
Lesley
L
Saklatvala
Jeremy
J
Dean
Jonathan L E
JL
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D005347:Fibroblasts; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000502:physiology*; D020871:RNA Stability; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D051546:Cyclooxygenase 2; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C057725:HSPB1 protein, human