Protein kinase cascades in intracellular signalling by interleukin-I and tumour necrosis factor.
Interleukin 1 (IL-1) and tumour necrosis factor (TNF) are major mediators of inflammation, with similar actions. Their receptor mechanisms and downstream pathways are reviewed. They activate several protein kinases in fibroblasts, including the three types of mitogen-activated protein kinase (MAPK), the kinase of the inhibitor of nuclear factor-kappa B (I kappa BK), and the TNF-/IL-1-activated beta-casein kinase. Cultured cells show a broader spectrum of kinase activation by IL-1 than tissues in vivo, suggesting that the receptors connect to more pathways in proliferating cells than in resting differentiated cells. The c-Jun N-terminal kinase (JNK) is strongly activated by IL-1 in tissues. In rabbit liver this is mediated by MAPK kinase 7; the upstream kinase is unidentified. Little is known of downstream MAPK targets in inflammation. Inhibitor experiments suggest that p38MAPK mediates induction of cyclo-oxygenase-2 and metalloproteinases by IL-1, and of TNF, IL-1 and cyclo-oxygenase-2 by endotoxin (in monocytes). p38MAPK is needed for induction of the mRNAs (except IL-1 mRNA).
Saklatvala
J
J
Division of Cell Signalling, Kennedy Institute of Rheumatology, Hammersmith, London, U.K.
Dean
J
J
Finch
A
A
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human