Signal transduction

The signal transduction pathways that couple surface receptor stimulation to inducible cytokine gene expression have been most extensively studied in T cells. The common theme that has emerged is that a variety of distinct pathways converge at the level of transcription factor regulation to control cytokine gene transcription. Pathways that might regulate post-transcriptional events arc much less well defined.

Three major signaling pathways activated by TCR ligation regulate cytokine production in T cells. These pathways and the transcription factors through which they act are as follows: 1) a calcium-dependent pathway regulating NFAT family members; 2) a protein kinase C (PKC)-dependent pathway that acts through AP-1 and NF-kB; 3) pathways activated by p21ras that work primarily through AP-1. The calcium-dependent and PKC pathways share a common activator, phospholipase-C-y-1. Tyrosine phosphorylation activates phospholipase C-y-1 resulting in the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol triphosphate and diacyl-glycerol. The released inositol triphosphates stimulate the release of calcium ions from intracellular stores, activating the calcium-calmodulin dependent serine/threonine phosphatase calcineurin, which dephosphorylates NFAT proteins, resulting in their translocation to the nucleus. The importance of this pathway is evidenced by the presence of NFAT consensus binding sites in the regulatory regions of all cytokine genes studied, and the devastating effect of the calcineurin inhibitor cyclosporin A upon cytokine production. Diacylglycerol activates PKC-a and -e isoforms, which activate cytokine gene expression via the NF-kB and AP-1 transcription factors. NF-kB activation is achieved by phosphorylation of the inhibitory subunit IkB, which promotes dissociation of IkB from the inactive cytosolic complex and allows the nuclear translocation of NF-kB. AP-1 regulation is achieved through activation of the MAP kinases, which are downstream effectors of both PKC and p21™.

Stimuli that affect T cell commitment to the production of particular cytokines, such as IL-12 for the promotion of type 1 responses and IL-4 for the promotion of type 2 responses, utilize a set of signaling molecules distinct from those activated by the TCR. These include members of the JAK family of tyrosine kinases and their substrates, the STAT transcription factors. There is evidence that the establishment of stable cytokine production phenotypes is associated with modulation of these signaling pathways.

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