Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds.
Recent work in this laboratory has identified immune-stimulatory properties of the oxidant hemin. In this study, we examined whether the nitrogen-based oxidant nitric oxide (NO) had inductive effects on human lymphocytes. We found that the NO-generating compounds sodium nitroprusside and S-nitroso-N-acetylpenicillamine rapidly enhanced the rate of glucose transport in resting human PBMC. In addition, NF-kappa B binding activity was induced by these agents as was the secretion of TNF-alpha. The data suggest that a cGMP-independent mechanism is involved as the cell permeant cGMP analogue, 8-Br-cGMP, had no effect in eliciting these inductive events. Activation of lymphocytes by these NO-generating compounds may be mediated through the protein tyrosine phosphorylation signal transduction pathway. We found that membrane-associated protein tyrosine phosphatase activity was enhanced in PBMC treated with sodium nitroprusside or S-nitroso-N-acetylpenicillamine and that the src family protein tyrosine kinase p56lck was activated in these cells. Inasmuch as p56lck activity is negatively controlled by tyrosine phosphorylation, its activation may be related to the enhancement of protein tyrosine phosphatase activity. 8-Br-cGMP had no effect on these enzymes. Taken together, these data suggest that NO may have immune-stimulatory properties and may signal through a hitherto undescribed cGMP-independent pathway.
Lander
H M
HM
Rogosin Institute, Cornell University Medical College, New York, NY 10021.
Sehajpal
P
P
Levine
D M
DM
Novogrodsky
A
A
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001692:Biological Transport; D003571:Cytochalasin B / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009569:Nitric Oxide; D003571:Cytochalasin B; D026423:S-Nitroso-N-Acetylpenicillamine; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017027:Protein Tyrosine Phosphatases; D010396:Penicillamine; D005947:Glucose