Induction of transcription factors in human T lymphocytes by aspirin-like drugs.
Aspirin-like drugs (ALD) induce calcium mobilization, an essential component of T cell activation, but do not induce the biosynthesis of IL-2. To understand the extent to which ALD may mimic mitogenic stimulation, we studied cytoplasmic and nuclear signaling steps in ALD-treated T cells. We found that ALD induce a transient activation of protein kinase (PKC) but have no effect (in comparison to anti-CD3 antibodies) on protein tyrosine phosphorylation nor on PCL gamma 1 tyrosine phosphorylation. ALD-induced calcium mobilization and PKC activation are independent of tyrosine protein kinase activity as shown by the lack of effect of herbimycin, a tyrosine-protein kinase-specific inhibitor. Although we detected no IL-2 mRNA in ALD-treated cells, the nuclei of these cells contain proteins capable of binding to three regulatory sequences in the IL-2 promoter region: NFAT, NF kappa B, and AP-1. These binding activities are expressed only in activated T cells. The expression of AP-1 depended on calcium mobilization and PKC activation. These data suggest that ALD cause transient but significant changes in T cell transmembrane signaling, although some events induced by stimulation with anti-CD3 antibodies are not induced by ALD. The signal is transmitted to the nucleus and induces DNA-binding activity by several transcription factors. However, the ALD stimulus is not capable of causing complete T cell activation.
Flescher
E
E
Department of Medicine, University of Texas Health Science Center at San Antonio 78284, USA.
Ledbetter
J A
JA
Ogawa
N
N
Vela-Roch
N
N
Fossum
D
D
Dang
H
H
Talal
N
N
D000328:Adult; D001483:Base Sequence; D016227:Benzoquinones; D002118:Calcium / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004008:Diclofenac / Q000494:pharmacology*; D005260:Female; D005480:Flurbiprofen / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016853:Muromonab-CD3 / Q000494:pharmacology; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D007527:Isoenzymes; D047029:Lactams, Macrocyclic; D016853:Muromonab-CD3; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011809:Quinones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004008:Diclofenac; D017828:Rifabutin; D005480:Flurbiprofen; C020754:herbimycin; D011493:Protein Kinase C; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D007052:Ibuprofen