Signalling platforms that modulate the inflammatory response: new targets for drug development.
Therapeutically controlling inflammation is essential for the clinical management of many high-prevalence human diseases. Drugs that block the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukin-1 (IL-1) can improve outcomes for rheumatoid arthritis and other inflammatory diseases but many patients remain refractory to treatment. Here we explore the need for developing new types of anti-inflammatory drugs and the emergence of novel drug targets based on the clustering of IL-1 receptors into multi-protein aggregates associated with cell adhesions. Interference with receptor aggregation into multi-protein complexes effectively abrogates IL-1 signalling. The exploration of the crucial molecules required for receptor clustering, and therefore signal transduction, offers new targets and scope for anti-inflammatory drug development.
McCulloch
Christopher A
CA
CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Canada M5S 3E2. christopher.mcculloch@utoronto.ca
Downey
Gregory P
GP
El-Gabalawy
Hani
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D020013:Calcium Signaling; D015195:Drug Design; D022001:Focal Adhesions; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases