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Figure 3. A model showing the regulation of CD38 expression by the inflammatory cytokine TNF-
and glucocorticoids in human airway smooth muscle cells. Activation of TNF receptor 1 (TNFR1) by TNF causes receptor trimerization, recruitment of an adaptor protein complex and a downstream signaling cascade, resulting in I
B phosphorylation, dissociation of the p50/p65 subunits of NF-B and their nuclear translocation to activate transcription of NF-B-dependent genes. Two possible modes of transcriptional regulation of cd38 are shown. A) Binding of the p50/p65 subunits of NF-B to response elements activates transcription of potential NF-B-dependent genes, which secondarily activate cd38 expression; B) Direct binding to response elements resulting in transactivation of cd38. Glucocorticoid (GC) binding to its receptor (GR) causes dissociation of the GR/heat shock protein complex, nuclear translocation of the GR homodimer and binding to glucocorticoid response element (GRE). Down-regulation of cd38 expression results from: transrepression of NF-B and potential NF-B-dependent genes; activation of IB transcription; direct binding to GRE motif within the cd38 to cause inhibition of transcription. Model also shows direct protein-protein interaction involving the GCR (GC bound to its receptor)/NF-B, which may result in mutual repression.
