[en] OBJECTIVES: We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND: Mechanical stress upregulates pro-inflammatory cytokines in the myocardium. METHODS: Fifteen infants with tetralogy of Fallot (TOF) (n = 7) or with ventricular septal defects (VSDs) (n = 8) were investigated. Concentrations of pro- and anti-inflammatory cytokines and of the inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay and/or Western blotting in the right ventricular myocardium taken during cardiac surgery. Activation of the nuclear factor-kappa-B (NF-kappa-B) and p38 mitogen-activated protein kinase (MAPK) pathways was assessed by electrophoretic mobility shift assay with supershift and/or Western blotting, respectively. RESULTS: The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6 and the anti-inflammatory cytokine IL-10 were detected in the myocardium of all patients. Concentrations of the pro-inflammatory cytokines and also of phosphorylated p38 MAPK were higher in patients with TOF than in those with VSD and correlated with the degree of pressure overload of the right ventricle. Levels of phosphorylated I-kappa-B-alpha, iNOS, and IL-10 were similar in patients with TOF and in those with VSD. CONCLUSIONS: Our results show intramyocardial synthesis of pro-inflammatory cytokines in infants with congenital cardiac defects. This is associated with activation of both the NF-kappa-B and p38 MAPK pathways. The latter could be particularly important for the transduction of mechanical signals in the infant's myocardium. Synthesis of IL-10 indicates an intramyocardial anti-inflammatory potential in this age group.
Disciplines :
Pediatrics
Author, co-author :
Qing, Ma; Technische Universität München - TUM > Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich
Schumacher, Kathrin; Technische Universität München - TUM > Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich
Heise, Ruth; Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Interdisciplinary Center for Clinical Research BIOMAT
Woltje, Michael; Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Interdisciplinary Center for Clinical Research BIOMAT
Vazquez-Jimenez, Jaime F; Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Thoracic and Cardiovascular Surgery
Richter, Thomas; Technische Universität München - TUM > Institute of Pathology
Vilcek J, Lee TH. Tumor necrosis factor: new insights into the molecular mechanisms of its multiple actions. J Biol Chem 1991;266:7313-6.
Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart. J Am Coll Cardiol 2001;38:307-14.
Herlaar E, Brown Z. p38 MAPK signalling cascades in inflammatory disease. Mol Med Today 1999;5:439-47.
Liang F, Gardner DG. Mechanical strain activates BNP gene transcription through a p38/NF-kappaB-dependent mechanism. J Clin Invest 1999;104:1603-12.
Kapadia SR, Oral H, Lee J, et al. Hemodynamic regulation of minor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res 1997;81:187-95.
Gurevitch J, Frolkis I, Yuhas Y, et al. Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion. J Am Coll Cardiol 1996;28:247-52.
Kunz M, Bloss G, Gillitzer R, et al. Hypoxia/reoxygenation induction of monocyte chemoattractant protein-1 in melanoma cells: involvement of nuclear factor-kappaB, stimulatory protein-1 transcription factors and mitogen-activated protein kinase pathways. Biochem J 2002;366:299-306.
Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol 1998;274:R577-95.
Vazquez-Jimenez JF, Qing M, Hermanns B, et al. Moderate hypothermia during cardiopulmonary bypass reduces myocardial cell damage and myocardial cell death related to cardiac surgery. J Am Coll Cardiol 2001;38:1216-23.
Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation 2000;101:1019-26.
Ertel W, Morrison MH, Ayala A, et al. Hypoxemia in the absence of blood loss or significant hypotension causes inflammatory cytokine release. Am J Physiol 1995;269:R160-6.
Hövels-Gürich HH, Schumacher K, Vazquez-Jimenez JF, et al. Cytokine balance in infants undergoing cardiac operation. (with discussion) Ann Thorac Surg 2002;73:601-9.
Schiffer R, Klein B, Klosterhalfen B, et al. The contact of human macrophages with extracellular matrix proteins selectively induces expression of proinflammatory cytokines. Pathobiology 1999;67:233-5.
Tabardel Y, Duchateau J, Schmartz D, et al. Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men. Surgery 1996;119:76-80.
Pulkki KJ. Cytokines and cardiomyocyte death. Ann Med 1997;29:339-43.
Hövels-Gürich HH, Vazquez-Jimenez JF, Silvestri A, et al. Production of proinflammatory cytokines and myocardial dysfunction after arterial switch operation in neonates with transposition of the great arteries. J Thorac Cardiovasc Surg 2002;124:811-20.
Naldini A, Carraro F, Silvestri S, et al. Hypoxia affects cytokine production and proliferative responses by human peripheral mononuclear cells. J Cell Physiol 1997;173:335-42.
Frangogiannis NG, Mendoza LH, Lindsey ML, et al. IL-10 is induced in the reperfused myocardium and may modulate the reaction to injury. J Immunol 2000;165:2798-808.
Schottelius AJ, Mayo MW, Sartor RB, et al. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem 1999;274:31868-74.
Kontoyiannis D, Kotlyarov A, Carballo E, et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. EMBO J 2001;20:3760-70.
Wong SC, Fukuchi M, Melnyk P, et al. Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure. Circulation 1998;98:100-3.
Mou SS, Haudek SB, Lequier L, et al. Myocardial inflammatory activation in children with congenital heart disease. Crit Care Med 2002;30:827-32.
Taylor BS, de Vera ME, Ganster RW, et al. Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem 1998;273:15148-56.
Kan H, Xie Z, Finkel MS. HIV gp120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-kappaB activation. Am J Physiol Heart Circ Physiol 2000;279:H3138-43.
Ferreiro CR, Chagas AC, Carvalho MH, et al. Influence of hypoxia on nitric oxide synthase activity and gene expression in children with congenital heart disease: a novel pathophysiological adaptive mechanism. Circulation 2001;103:2272-6.
Wildhirt SM, Suzuki H, Horstman D, et al. Selective modulation of inducible nitric oxide synthase isozyme in myocardial infarction. Circulation 1997;96:1616-23.
Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387-9.
Takano H, Manchikalapudi S, Tang XL, et al. Nitric oxide synthase is the mediator of late preconditioning against myocardial infarction in conscious rabbits. Circulation 1998;98:441-9.