Interleukin 1 and Tumor Necrosis Factor Inhibit Cardiac Myocyte β -adrenergic Responsiveness

Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured ca...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1989-09, Vol.86 (17), p.6753-6757
Main Authors: Gulick, Tod, Chung, Mina K., Pieper, Stephen J., Lange, Louis G., Schreiner, George F.
Format: Article
Language:English
Subjects:
Agonists
Amnion - cytology
Animals
Animals, Newborn
beta -adrenergic
Biological and medical sciences
Cell culture techniques
Cell physiology
Cells, Cultured
Cellular immunity
Cultured cells
Cyclic AMP - metabolism
Cytokines
Epithelial Cells
Female
Fundamental and applied biological sciences. Psychology
Guanine nucleotides
Heart - drug effects
Heart - physiology
Humans
interleukin 1
Interleukin-1 - pharmacology
Isoproterenol - pharmacology
Kinetics
Lymphocyte Culture Test, Mixed
Lymphocytes - immunology
Molecular and cellular biology
Muscle Contraction
Muscle, Smooth - cytology
Myocardial Contraction - drug effects
Myocardium
Myocardium - metabolism
Pregnancy
Rats
Rats, Inbred Lew
Rats, Inbred Strains
Receptors
Receptors, Adrenergic, beta - drug effects
Receptors, Adrenergic, beta - metabolism
Receptors, Adrenergic, beta - physiology
Responses to growth factors, tumor promotors, other factors
Sarcolemma - metabolism
Splenocytes
tumor necrosis factor
Tumor Necrosis Factor-alpha - pharmacology
Tumor necrosis factors
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Summary:Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit β -adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in β -adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that β -receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.86.17.6753