Role of protein kinase pathways in IL-1-induced chemoattractant expression by human mesangial cells.
Human mesangial cells produce the monocyte-specific chemotactic factor monocyte chemoattractant protein-1 (MCP-1) in response to a variety of stimuli, including the pro-inflammatory cytokine interleukin-1 beta (IL-1). The intracellular signals responsible for mediating the effects of IL-1 on MCP-1 expression in human mesangial cells have not been defined. Evidence from other types of cells suggests that protein kinases are involved in MCP-1 gene regulation. We investigated the role of protein kinase pathways in mediating IL-1-induced MCP-1 expression. Activation of protein kinase C (PKC) by phorbol esters or diacyglycerol up-regulated mesangial MCP-1 message and bioactivity in a fashion similar to IL-1. However, while inhibition of PKC activity completely blocked phorbol-induced MCP-1 up-regulation, induction by IL-1 was not prevented. Inhibitors of cyclic AMP (cAMP)-dependent protein kinase (PKA) also failed to block IL-1-induced MCP-1 expression. Furthermore, increasing intracellular cAMP and activating PKA attenuated basal MCP-1 mRNA levels by 82% and blocked IL-1 induced MCP-1 expression by 88%. Finally, the role of protein tyrosine kinases was studied. The structurally distinct protein tyrosine kinase (PTK) inhibitors genistein, herbimycin A, and tyrphostin each caused a dose-dependent inhibition of the effects of IL-1 on mesangial MCP-1 activity. IL-1 treatment of mesangial cells resulted in the up-regulation of three tyrosine phosphoproteins with apparent molecular masses between 40 and 62 kD. These results suggest that the effects of IL-1 on MCP-1 expression are not mediated through PKC or cAMP-PKA, but may be transduced through PTKs.
Rovin
B H
BH
Department of Medicine, Ohio State University School of Medicine, Columbus.
Tan
L C
LC
D002478:Cells, Cultured; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D018932:Chemokine CCL2; D002630:Chemotactic Factors; D007375:Interleukin-1; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C