RT Journal Article
SR Electronic
T1 Role of p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Protein Kinase Kinase in Adenosine A<sub>2B</sub>Receptor-Mediated Interleukin-8 Production in Human Mast Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 726
OP 734
VO 55
IS 4
A1 Igor Feoktistov
A1 Anna E. Goldstein
A1 Italo Biaggioni
YR 1999
UL http://molpharm.aspetjournals.org/content/55/4/726.abstract
AB The endogenous nucleoside adenosine is thought to play a role in the pathophysiology of asthma by stimulating mast cells. We previously showed that the human mast cell line HMC-1 expresses A2Aand A2B receptors, and that both receptors activate adenylate cyclase via Gs-protein but that only A2B receptors are also coupled to phospholipase C via Gq proteins. Stimulation of A2B but not A2A receptors induced production of interleukin-8 (IL-8) from HMC-1 cells. The mechanism by which adenosine promotes IL-8 synthesis has not been defined. In this study, we tested the hypothesis that mitogen-activated protein kinase (MAPK) signaling pathways are involved in this process. Stimulation of HMC-1 with the stable adenosine analog NECA (5′-N-ethylcarboxamidoadenosine) activated p21ras and both p42 and p44 isoforms of extracellular signal-regulated kinase (ERK). NECA (10 μM) induced a 1.9 ± 0.06-fold increase in ERK activity, whereas 10 μM of the selective A2A agonist CGS 21680 (4-((N-ethyl-5′-carbamoyladenos-2-yl)-aminoethyl)-phenylpropionic acid) had no effect. NECA, in parallel with the activation of ERK, also stimulated the p46 isoform of c-Jun N-terminal kinase (MEK) and p38 MAPK. Furthermore, the selective MAPK/ERK kinase 1 inhibitor PD 98059 (2′-amino-3′-methoxyflavone), and p38 MAPK inhibitors SB 202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole) and SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole) blocked A2B receptor-mediated production of IL-8. These results indicate that extracellular adenosine can regulate ERK, c-Jun N-terminal kinase, and p38 MAPK signaling cascades and that activation of ERK and p38 MAPK pathways are essential steps in adenosine A2B receptor-dependent stimulation of IL-8 production in HMC-1. The American Society for Pharmacology and Experimental Therapeutics