Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway

• Published in: The Journal of biological chemistry Vol. 269; no. 13; pp. 9811 - 9816
• Main Authors: KOLB, J. P, PAUL-EUGENE, N, DAMAIS, C, YAMAOKA, K, DRAPIER, J. C, DUGAS, B
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 01.04.1994
• Subjects: Amino Acid Oxidoreductases - blood; Aminoquinolines - pharmacology; Analysis of the immune response. Humoral and cellular immunity; Arginine - analogs & derivatives; Arginine - blood; Arginine - pharmacology; Biological and medical sciences; Calcium - blood; Cells, Cultured; Cyclic GMP - blood; Dose-Response Relationship, Drug; Egtazic Acid - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Guanylate Cyclase - antagonists & inhibitors; Guanylate Cyclase - pharmacology; Humans; Immunobiology; Interferon-gamma - pharmacology; Interleukin-4 - pharmacology; Kinetics; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Leukocytes, Mononuclear - metabolism; Lymphokines, interleukins ( function, expression); Methylene Blue - pharmacology; Nitric Oxide Synthase; Nitroprusside - pharmacology; omega-N-Methylarginine; Regulatory factors and their cellular receptors; Human; Signal transduction; Interleukin 4; Monocyte; Enzyme; Cytokine; Nucleotide; Biosynthesis; Oxidoreductases; GMP; Nitric-oxide synthase; Gamma interferon
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(17)36955-7

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.