Exogenous nitric oxide regulates cyclooxygenase-2 expression and prostaglandin D(2) generation through p38 MAPK in mouse bone marrow-derived mast cells.
Nitric oxide (NO) is an important signaling molecule that regulates MC function. However, the involvement of NO in an important lipid mediator, prostaglandin (PG) D(2) production by MC, is unclear. The role of NO in cyclooxygenase (COX)-2 expression and PGD(2) generation as well as IL-6 production in mouse bone marrow-derived MC (BMMC) was investigated using NO donors. Exogenous NO augmented COX-2 protein expression and increased COX-2-dependent PGD(2) generation in response to SCF, IL-10, and IL-1beta, or antigen activation in combination with IL-10 and IL-1beta after sensitization with IgE. The increased expression of COX-2 by NO donors was inhibited by hemoglobin. Moreover it was not affected by soluble guanylyl cyclase inhibitor, but reduced by the p38 MAPK inhibitor, SB202190. Downstream of p38 MAPK, NO donors augmented not only COX-2 mRNA transcription but also its stability. Exogenous NO also augmented IL-6 production by SCF, IL-10, and IL-1beta. These results show that exogenous NO can increase COX-2-dependent PGD(2) and IL-6 production by MC in inflammatory environments through the p38 MAPK pathway. Therefore, our novel observations suggest that the effect of NO on MC is not limited to the suppression of their activation as has been the emphasis previously, but can also augment certain MC responses.
Moon
Tae Chul
TC
Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Befus
A Dean
AD
D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects* / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D015850:Interleukin-6; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2