Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway.
Nitric oxide (NO) has been invoked as an important pathogenic factor in a wide range of immunologically mediated diseases. The present study demonstrates that macrophage-derived NO may conversely function to fine tune T cell-mediated inflammation via reversible dephosphorylation of intracellular signaling molecules, which are involved in the control of T cell proliferation. Thus, T cells activated in the presence of alveolar macrophages are unable to proliferate despite expression of IL-2R and secretion of IL-2. This process is reproduced by the NO generator S-nitroso-N-acetylpenicillamine and is inhibitable by the NO synthase inhibitor N(G)-methyl-L-arginine. Analysis of T cell lysates by immunoprecipitation with specific Abs and subsequent immunoblotting indicated marked reduction of tyrosine phosphorylation of Jak3 and STAT5 mediated by NO. Further studies indicated that NO-mediated T cell suppression was reversible by the guanylate cyclase inhibitors methylene blue and LY-83583 and was reproduced by a cell-permeable analogue of cyclic GMP, implicating guanylate cyclase activation as a key step in the inhibition of T cell activation by NO.
Bingisser
R M
RM
TVW Telethon Institute for Child Health Research, Division of Cell Biology, West Perth, Australia.
Tilbrook
P A
PA
Holt
P G
PG
Kees
U R
UR
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017635:Clonal Anergy / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D053616:Janus Kinase 3; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology*; D008894:Milk Proteins; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D026423:S-Nitroso-N-Acetylpenicillamine; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism*
D000634:Aminoquinolines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C507936:Jak3 protein, rat; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; C041715:6-anilino-5,8-quinolinedione; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3; D000254:Sodium-Potassium-Exchanging ATPase; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester