Gulick T, Chung M K, Pieper S J, Lange L G, Schreiner G F
Department of Medicine, Jewish Hospital of Saint Louis, Washington University Medical Center, MO 63110.
Proc Natl Acad Sci U S A. 1989 Sep;86(17):6753-7. doi: 10.1073/pnas.86.17.6753.
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 beta-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 beta-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 beta-receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.
可逆性充血性心力衰竭可伴随心脏移植排斥反应和炎症性心肌炎，这些病症与心肌的免疫细胞浸润有关。为了确定免疫细胞分泌产物在无细胞毒性的情况下是否会改变心肌代谢，我们在活化免疫细胞的培养上清液存在的情况下培养心肌细胞。我们观察到，这些培养上清液会抑制β-肾上腺素能激动剂介导的培养心肌细胞收缩性增加和细胞内cAMP积累。预先暴露于这些培养上清液后，心肌细胞对细胞外Ca2+浓度升高的收缩反应未改变，对直接腺苷酸环化酶激活剂福斯可林刺激的心肌细胞内cAMP浓度升高也未改变。抑制作用在β-肾上腺素能受体密度或配体结合亲和力未改变的情况下发生。抑制活性归因于巨噬细胞衍生的细胞因子白细胞介素1和肿瘤坏死因子。因此，这些观察结果描述了特定细胞因子在调节收缩细胞的激素反应性和功能中的作用。白细胞介素1和肿瘤坏死因子对细胞内cAMP积累的影响可能是依赖于环核苷酸代谢的其他细胞功能免疫调节的模型。激动剂占据的受体与腺苷酸环化酶的解偶联表明，细胞因子对心肌细胞的直接或间接作用改变了β受体或鸟嘌呤核苷酸结合蛋白的功能。
