ADAM10 (MADM), ADAM12 (mdc9) and ADAM15 (metargidin) gene expression in the U937 human histiocytic lymphoma cell line: Regulation of gene expression by IL10, IL4 and PMA

摘要

The ADAM family of proteins have a complex domain structure containing both metalloproteinase and cell adhesion domains as well as several other C-terminal domains with amino acid sequence similarity to proteins such as the epidermal growth factor (EGF) and thrombospondin. This multi-domain structure has led to proposals implicating ADAM proteins in various cell-cell and cell-matrix interactions including cytokine receptor shedding phenomena, cell fusion reactions, and modification of proteinaceous components of the extracellular matrix. Published data [Williams, L.M., Gibbons, D.L., Gearing, A., Maini, R.N., Feldmann, M. and Brennan, F.M. (1996) Journal of Clinicallnvestigation 97, 2833-2841] on the metalloproteinase catalysed reaction which mediates TNF receptor(s) shedding in response to IL10 and IL4 in U937 cells led us to investigate ADAM gene regulation with these cytokines in an attempt to implicate ADAM metalloproteinase domains in this process. We present herein that transcription of the ADAM10 gene is increased by stimulation with IL10. ADAM12 also demonstrates transcriptional regulation by IL10 but shows a slower response with respect to time. IL4 however decreases transcription of the mRNA for both ADAM10 and ADAM12. The effects of IL4 on ADAM10 transcription appear to be mediated solely through the ablation of the larger of the two ADAM10 mRNA transcripts. ADAM15 shows no obvious transcriptional regulation by either IL10 or IL4 under conditions employed here. In experiments using the tumour promoting agent phorbol 12-myristate 13-acetate (PMA) we also demonstrate stimulation of transcription of the genes for ADAM10 and ADAM12 but show that the ADAM15 gene is repressed by treatment with this agent. The regulation of the transcription of the ADAM 10 and ADAM12 genes corresponds well with the expression profile of the PMA inducible metalloproteinase responsible for shedding TNF receptors in U937 cells. We propose that this demonstrated cytokine regulation of ADAM10 and ADAM12 gene transcription may reflect a role for these proteins either directly or as part of a catalytic cascade culminating in the shedding of the TNFa receptor(s).-