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Immunopharmacology of inflammation
628
Abstracts
STREPTOZOTOCIN F.B. De B r i t o .
INDUCED IMMUNOSUPPRESSION IN R A T S Imperial Chemical Industries, Alderley
18 Park,
Cheshire
UK
T h e i m m u n e s t a t u s of d i a b e t i c rats was examined to s h e d s o m e l i g h t on the often assumed association of d i a b e t e s with increased susceptibility to infection. Rats with established hyperglycaemia as a r e s u l t of 6 O m g / k g i.v. d a y - 3 S t r e p t o z o t o c i n had thymus:body weight ratios that were markedly l o w e r t h a n t h a t of n o n - d i a b e t l c control rats whereas spleen:body weight ratios were relatively less affected. The serum sgglutin response to iv s h e e p r e d b l o o d c e l l s w a s s i m i l a r in b o t h g r o u p s b u t d i a b e t i c rats failed to m o u n t d e l a y e d skin reactions to e g g a l b u m i n and were extremely susceptible to s y s t e m i c injection with Listeria monoc~to~enes and C a n d i d a albicans. The non-specific acute inflammatory reaction to e a r r a g e e n a n in t h e p a w of d i a b e t i c rats was however more intense as w a s p a s s i v e acute experimental glomerulonephrltls, J u d g e d by the v o l u m e of u r i n e and t o t a l protein excreted. A l s o if C . a l b ~ c a n s w a s g i v e n w i t h the a n t i - g l o m e r u l a r basement membrane serum there was a proportionately greater reduction in renal candidal counts in d i a b e t i c rats. The data indicates that while cell-mediated immune defences in d i a b e t i c r a t s is h e a v i l y suppressed, nonspecific and humoral immune defences which appear intact may account for the prolonged survival of t h e s e r a t s . PUYSIOLOGICAL
CONCENTRATIONS OF ZINC MODULATE TIIE DE NOVO SYNTHESIS OF ARACHIDONIC ACID 2 9 METABOLITES FROM h"JMAN BASOPHILS AND LUNG MAST CELLS
G. Marone, M. Columbo~ A. de Paulis, R. Cirillo, R. Giugliano and M. Condorelli Department of Medicine - University of Naples II School of Medicine,
80131 Naples,
Italy
We have shown that physiological concentrations of zinc inhibit the release of histamine from human basophil leukocytes (Marone et al., J. Pharmacol. Exp. Ther. 217:292, 1981). In these experiments we have evaluated the effect of zinc on the release of chemical mediators from mast cells isolated from human lung. Zinc chloride (10 -6 - 3 x 10 -5 M) did not affect spontaneous release of LDH or histamine from human lung mast cells. Preincubation (5 min, 37°C) of lung mast cells with zinc chloride (10 -6 -3 x 10 -5 M) caused a dose-dependent inhibition of anti-lgE-mediated histamine release. The inhibitory effect of zinc was completely abolished by washing the cells before anti-lgE challenge. Increasing Ca 2+ concentrations (0.3 to 6 mM) in the extracellular medium completely reversed the inhibitory effect of zinc on anti-lgE-mediated histamine secretion. Zinc is a competitive antagonist of the action of Ca 2+ in histamine secretion induced by anti-lgE with a dissociation constant of about 10 -5 M. These findings indicate that physiological concentrations of zinc inhibit the release of histamine from human basophils and lung mast cells presumably by blocking the Ca 2+ uptake induced by snti-lgE activation. MODULATION
OF
TIIE RELEASE
OF
CHEMICAL MEDIATORS AURANOFIN
FROM
h~UMAN INFLAMMATORY
CELLS
BY 3 0
G. Marone, M. Co]umbo~ D. Galeone, G. Guidi, A. Kagey-Sobotka and L.M. Lichtenstein Department of Medicine - University of Naples II School of Medicine, 80131 Naples, Italy and Division of Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21239~ USA Auranofin, a new orally absorbable gold compound, is effective in the treatment of patients with rheumatoid arthritis. We have evaluated the effect of pharmacological concentrations of auranofin on the release of chemical mediators from human inflammatory cells. Auranofin (10 -6 10 -5 M) caused a dose-dependent inhibition of histamine and leukotriene C 4 (LTC 4) release from human basophils induced by antigen and anti-lgE. The inhibitory effect of auranofin on IgE-mediated histamine release from basophils was irreversible and not influenced by the presence or absence of extracellular Ca 2+. Auranofin (10 -6 10 -5 M) inhibited the anti-lgE-induced release of LTC4, PGD 2 and histamine from mast cells purified from human lung. In a final series of experiments auranofin (10 -6 - 10 -5 M) inhibited the release of LTC4~ lysosomal enzymes, 02 - and thromboxane B 2 from human polymorphonuclear leukocytes. These results indicate that auranofin, in pharmacological concentrations~ is a potent inhibitor of the release of chemical mediators from human inflammatory cells,
Abstracts
STREPTOZOTOCIN F.B. De B r i t o .
INDUCED IMMUNOSUPPRESSION IN R A T S Imperial Chemical Industries, Alderley
18 Park,
Cheshire
UK
T h e i m m u n e s t a t u s of d i a b e t i c rats was examined to s h e d s o m e l i g h t on the often assumed association of d i a b e t e s with increased susceptibility to infection. Rats with established hyperglycaemia as a r e s u l t of 6 O m g / k g i.v. d a y - 3 S t r e p t o z o t o c i n had thymus:body weight ratios that were markedly l o w e r t h a n t h a t of n o n - d i a b e t l c control rats whereas spleen:body weight ratios were relatively less affected. The serum sgglutin response to iv s h e e p r e d b l o o d c e l l s w a s s i m i l a r in b o t h g r o u p s b u t d i a b e t i c rats failed to m o u n t d e l a y e d skin reactions to e g g a l b u m i n and were extremely susceptible to s y s t e m i c injection with Listeria monoc~to~enes and C a n d i d a albicans. The non-specific acute inflammatory reaction to e a r r a g e e n a n in t h e p a w of d i a b e t i c rats was however more intense as w a s p a s s i v e acute experimental glomerulonephrltls, J u d g e d by the v o l u m e of u r i n e and t o t a l protein excreted. A l s o if C . a l b ~ c a n s w a s g i v e n w i t h the a n t i - g l o m e r u l a r basement membrane serum there was a proportionately greater reduction in renal candidal counts in d i a b e t i c rats. The data indicates that while cell-mediated immune defences in d i a b e t i c r a t s is h e a v i l y suppressed, nonspecific and humoral immune defences which appear intact may account for the prolonged survival of t h e s e r a t s . PUYSIOLOGICAL
CONCENTRATIONS OF ZINC MODULATE TIIE DE NOVO SYNTHESIS OF ARACHIDONIC ACID 2 9 METABOLITES FROM h"JMAN BASOPHILS AND LUNG MAST CELLS
G. Marone, M. Columbo~ A. de Paulis, R. Cirillo, R. Giugliano and M. Condorelli Department of Medicine - University of Naples II School of Medicine,
80131 Naples,
Italy
We have shown that physiological concentrations of zinc inhibit the release of histamine from human basophil leukocytes (Marone et al., J. Pharmacol. Exp. Ther. 217:292, 1981). In these experiments we have evaluated the effect of zinc on the release of chemical mediators from mast cells isolated from human lung. Zinc chloride (10 -6 - 3 x 10 -5 M) did not affect spontaneous release of LDH or histamine from human lung mast cells. Preincubation (5 min, 37°C) of lung mast cells with zinc chloride (10 -6 -3 x 10 -5 M) caused a dose-dependent inhibition of anti-lgE-mediated histamine release. The inhibitory effect of zinc was completely abolished by washing the cells before anti-lgE challenge. Increasing Ca 2+ concentrations (0.3 to 6 mM) in the extracellular medium completely reversed the inhibitory effect of zinc on anti-lgE-mediated histamine secretion. Zinc is a competitive antagonist of the action of Ca 2+ in histamine secretion induced by anti-lgE with a dissociation constant of about 10 -5 M. These findings indicate that physiological concentrations of zinc inhibit the release of histamine from human basophils and lung mast cells presumably by blocking the Ca 2+ uptake induced by snti-lgE activation. MODULATION
OF
TIIE RELEASE
OF
CHEMICAL MEDIATORS AURANOFIN
FROM
h~UMAN INFLAMMATORY
CELLS
BY 3 0
G. Marone, M. Co]umbo~ D. Galeone, G. Guidi, A. Kagey-Sobotka and L.M. Lichtenstein Department of Medicine - University of Naples II School of Medicine, 80131 Naples, Italy and Division of Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21239~ USA Auranofin, a new orally absorbable gold compound, is effective in the treatment of patients with rheumatoid arthritis. We have evaluated the effect of pharmacological concentrations of auranofin on the release of chemical mediators from human inflammatory cells. Auranofin (10 -6 10 -5 M) caused a dose-dependent inhibition of histamine and leukotriene C 4 (LTC 4) release from human basophils induced by antigen and anti-lgE. The inhibitory effect of auranofin on IgE-mediated histamine release from basophils was irreversible and not influenced by the presence or absence of extracellular Ca 2+. Auranofin (10 -6 10 -5 M) inhibited the anti-lgE-induced release of LTC4, PGD 2 and histamine from mast cells purified from human lung. In a final series of experiments auranofin (10 -6 - 10 -5 M) inhibited the release of LTC4~ lysosomal enzymes, 02 - and thromboxane B 2 from human polymorphonuclear leukocytes. These results indicate that auranofin, in pharmacological concentrations~ is a potent inhibitor of the release of chemical mediators from human inflammatory cells,