The Interleukin 1 Receptor: Ligand Interactions and Signal Transduction
Section snippets
Interleukin 1 (IL-1) is a multifunctional pro-inflammatory cytokine, that affects most cell types and results in numerous effects including: fever; increased hepatic acute phase response; increased metastases; angiogenesis; increased antibody and lymphokine production; cartilage breakdown; proliferation of fibroblasts, smooth muscle cells and mesangial cells; and increased HIV-1 gene expression [1]. Prior to 1984, when the cDNA for human IL-1β was first cloned [2], the activities that had been
Only the type I receptor (IL-1RI) directly binds IL-1 for signal transduction
Two different IL-1 receptors, types I and II, have been cloned and characterized [6]. Both receptors possess three conserved ecto- (i.e., extra-cellular) Ig-like domains responsible for binding ligand. Both bind IL-1 in the absence of other proteins. However, only the type I receptor, which possesses a long cytoplasmic sequence, appears to be able to transduce cellular signal events [7]. The type II receptor, which contains fewer than 30 cytoplasmic amino acids and binds to a collection of
The IL-1 receptor induces many signals
Numerous signal events have been reported to be elicited in an IL-1-dependent fashion and second messengers such as cyclic AMP, ceramide and protein kinase C have been implicated (see [1] for a review). Many of these effects are almost anecdotal, appear to be cell-type-dependent and have not yet been directly connected to the IL-1 receptor. Some of these events could represent indirect effects relating to cross-talk with other signaling pathways as well as delayed effects occurring many hours
Transcription factors and target genes
As described above, numerous transcription factors are activated in response to IL-1 receptor-mediated signaling and are responsible for the induction of many target genes. In addition to NF-κB and the MAPK responsive factors, at least three other factors have been reported to be activated by IL-1. The best known of these is C/EBPβ (also known as NF-IL6), a bZIP family factor which has been shown by our group and others to be responsive to activation by IL-1, IL-6 and LPS 66, 67, 68, 69.
Epilogue
The IL-1R signal transduction system has begun to yield to investigation after many years of little progress. The early, unlikely, concept that there was only a single receptor type that did not engage in a higher-order complex has been transformed into a large family of related molecules that either form heterodimers responsible for specific signaling or (in the apparent case of IL-18 and LPS) generate alternate receptor complexes that can recognize distinct ligands. This explains, in part,
Acknowledgements
Acknowledgements:We wish to acknowledge the assistance of those who assisted in the unpublished work described in this review. This includes members of the Cantley, Toker, Marmiroli, Gehrke and Krane labs as well as Russel Smith who initiated the PI3K studies in our group and carried out work on the IL-1β(Δ51–56) loop minus protein. Lorna Tsay is acknowledged for secretarial assistance. Structure coordinates were obtained from the Brookhaven Protein Database. Molecular modeling and display used
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The New England Baptist Bone and Joint Institute at The Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Ma 02115, USA.