Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway.
Resting human blood monocytes from some donors were found to produce a small amount of 3'-5' guanine cyclic monophosphate (cGMP) in response to interleukin 4 (IL-4). A much higher response was observed when monocytes were preincubated with interferon (IFN-gamma), which alone was ineffective. Preincubation of monocytes with IL-4 led, in contrast, to their subsequent incapacity to generate cGMP in response to IL-4. The accumulation of cGMP induced by IL-4 in IFN-gamma preincubated monocytes was dose-dependent and peaked about 15 min after its addition. It was inhibited in the presence of NG-mono-methyl-L-arginine (L-NMMA), an inhibitor of the nitric oxide synthase pathway. This suppressive effect of L-NMMA was reverted by an excess of L- but not of D-arginine. Accumulation of cGMP was significantly reduced by addition of soluble guanylyl cyclase inhibitors, such as LY83583 [correction of LY83853] and methylene blue, but was not impaired in the presence of EGTA, suggesting that the pathway involved is calcium independent. In addition, IL-4 induced an increased secretion of nitrite by monocytes, that was potentiated by IFN-gamma and inhibited by L-NMMA. Taken together, these results suggest that the sequential exposure of monocytes to IFN-gamma and IL-4 elicits the release of NO from L-arginine, which in turn is capable to stimulate soluble guanylyl cyclase.
Kolb
J P
JP
Institut National de la Santé et de la Recherche Médicale U365, Institut Curie, Paris, France.
Paul-Eugene
N
N
Damais
C
C
Yamaoka
K
K
Drapier
J C
JC
Dugas
B
B
D000594:Amino Acid Oxidoreductases / Q000097:blood*; D000634:Aminoquinolines / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008751:Methylene Blue / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D009599:Nitroprusside / Q000494:pharmacology; D019323:omega-N-Methylarginine
D000634:Aminoquinolines; D009599:Nitroprusside; D015847:Interleukin-4; D019323:omega-N-Methylarginine; D004533:Egtazic Acid; D007371:Interferon-gamma; C041715:6-anilino-5,8-quinolinedione; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium; D008751:Methylene Blue