       Document 0006
 DOCN  M9610006
 TI    Defective signal-transduction pathways in T-cells from autoimmune
       MRL-lpr/lpr mice are associated with increased polyamine concentrations.
 DT    9601
 AU    Thomas TJ; Gunnia UB; Seibold JR; Thomas T; Clinical Research Center,
       University of Medicine and Dentistry of; New Jersey-Robert Wood Johnson
       Medical School, New Brunswick; 08903, USA.
 SO    Biochem J. 1995 Oct 1;311 ( Pt 1):175-82. Unique Identifier : AIDSLINE
       MED/96003913
 AB    We previously reported that difluoromethylornithine (DFMO), an inhibitor
       of polyamine biosynthesis, exerted significant beneficial effects on the
       lifespan and disease expression of MRL-lpr/lpr mice, which spontaneously
       develop a lupus-like syndrome. Polyamine levels in splenic T-cells of
       MRL-lpr/lpr mice were significantly higher than those of Balb/c mice. In
       the present investigation, we examined the role of endogenous polyamines
       in transmembrane Ca2+ influx, generation of InsP3 and tyrosine
       phosphorylation of the p56lck protein in concanavalin A-stimulated
       splenic T-cells. Cytosolic free calcium concentrations ([Ca2+]i) in
       concanavalin A-stimulated T-cells of MRL-lpr/lpr and Balb/c mice were
       250 +/- 25 and 450 +/- 42 nM respectively. Treatment of MRL-lpr/lpr mice
       with DFMO increased [Ca2+]i to 360 +/- 30 nM (P < 0.05). InsP3 levels of
       concanavalin A-stimulated MRL-lpr/lpr splenic T-cells were only 20%
       higher than those of unstimulated controls, whereas those of Balb/c
       T-cells were 90% higher. DFMO treatment increased InsP3 levels in
       concanavalin A-treated MRL-lpr/lpr T-cells to 67%. Western-blot analysis
       showed a 7-fold higher level of p56lck phosphorylation of MRL-lpr/lpr
       splenic T-cells than that of Balb/c mice. DFMO treatment reduced
       tyrosine phosphorylation of p56lck of MRL-lpr/lpr mice significantly (P
       < 0.001). Two-colour flow-cytometric analysis revealed no significant
       difference in the CD4+/CD8+ ratio in splenic T-cells of MRL-lpr/lpr mice
       after DFMO treatment. Polyamine levels in splenocytes were significantly
       reduced by DFMO treatment. These data show that DFMO treatment could
       alter signal-transduction pathways of splenic T-cells of MRL-lpr/lpr
       mice. Increased levels of polyamines in T-cells of untreated lpr mice
       contribute to defective signal-transduction pathways and the
       pathogenesis of lupus-like symptoms.
 DE    Animal  Autoimmune Diseases/*PHYSIOPATHOLOGY  Blotting, Western
       Calcium/METABOLISM  Concanavalin A/PHARMACOLOGY  CD4-CD8 Ratio
       Eflornithine/PHARMACOLOGY  Female  Inositol Phosphates/METABOLISM  Lupus
       Erythematosus, Systemic/PHYSIOPATHOLOGY  Mice  Mice, Inbred BALB C
       Ornithine Decarboxylase/METABOLISM  Phosphorylation
       Phosphotyrosine/METABOLISM  Polyamines/ANTAGONISTS & INHIB/METABOLISM
       *Signal Transduction  Spleen/CYTOLOGY  Support, Non-U.S. Gov't  Support,
       U.S. Gov't, P.H.S.  T-Lymphocytes/DRUG EFFECTS/PATHOLOGY/*PHYSIOLOGY
       JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

