INTRACELLULAR SIGNALING MECHANISMS OF INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR - POSSIBLE TARGETS FOR THERAPY

Interleukin 1 (IL-1) and tumour necrosis factor (TNF) are primary inflammatory cytokines. They have highly similar diverse biological actions and act as local and systemic hormones to cause many features of inflammation. Results of studies in animals and humans indicate that blocking their production or action will have marked anti-inflammatory effects. They combine with distinct receptors at the cell surface and rapidly activate intracellular protein kinase cascades. The protein kinases then phosphorylate a variety of cellular protein substrates, including transcription factors, to produce the biological response. In cell culture IL-1 and TNF have the potential to activate all three MAP (Mitogen-Activated Protein) kinase cascades, as well as other less well characterized enzymes. The mechanism(s) by which the cytokine receptors activate the kinases is unknown. There is some evidence that IL-1 and TNF activate sphingomyelinase in the cell membrane to generate ceramide, which may have a signalling function.