Vol 59, No 3 (2021)
Original paper
Published online: 2021-09-20
IL-39 increases ROS production and promotes the phosphorylation of p38 MAPK in the apoptotic cardiomyocytes
Abstract
Introduction. The cytokine interleukin (IL)-39 is a novel member of the IL-12 family. Our previous study found that the serum level of IL-39 significantly increased in patients with acute myocardial infarction. However, the role of IL-39 in cardiomyocyte apoptosis remains unclear.
Material and methods. In this study, the cultured mouse HL-1 cardiomyocytes were incubated with PBS, 0-100 ng/mL IL-39, 200 μM H2O2 or 20 μM Trolox.
Results. IL-39 promoted the production of intracellular reactive oxygen species (ROS) in a concentration dependent manner in HL-1 cardiomyocytes. IL-39 and H2O2 both significantly promoted the production of intracellular ROS, increased the level of intracellular CCL2, stimulated the apoptotic progress of cardiomyocytes, increased the mRNA and protein expression levels of Bax, caspase-3, and p-p38 MAPK, and decreased the mRNA and protein expression levels of Bcl-2. ROS production, CCL2 level, cardiomyocyte apoptosis, and expression of Bax, caspase-3, and p-p38 MAPK were significantly amplified by the administration of IL-39 combined with H2O2, and these processes were significantly alleviated by an antioxidant Trolox.
Conclusion. This study was novel in revealing that IL-39 promoted apoptosis by stimulating the phosphorylation of p38 MAPK in mouse HL-1 cardiomyocytes.
Keywords: apoptosisHL-1 cardiomyocyteinterleukin-39p38 MAPKROS
References
- Herrett E, Bhaskaran K, Timmis A, Denaxas S, Hemingway H, Smeeth L. Association between clinical presentations before myocardial infarction and coronary mortality: a prospective population-based study using linked electronic records. Eur Heart J. 2014;35(35):2363-2371. .
- van Do, Sonnenschein K, Nieuwlaat R, et al. Sustained benefit 20 years after reperfusion therapy in acute myocardial infarction. J Am Coll Cardiol. 2005;46(1):15-20. .
- Hausenloy DJ, Botker HE, Engstrom T, et al. Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations. Eur Heart J. 2017; 38(13): 935–941.
- Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J. 2017; 38(11): 774–784.
- Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev. 2007; 59(4): 418–458.
- Davidson SM, Ferdinandy P, Andreadou I, et al. CARDIOPROTECTION COST Action (CA16225). Multitarget Strategies to Reduce Myocardial Ischemia/Reperfusion Injury: JACC Review Topic of the Week. J Am Coll Cardiol. 2019; 73(1): 89–99.
- Lin Li, Knowlton AA. Innate immunity and cardiomyocytes in ischemic heart disease. Life Sci. 2014; 100(1): 1–8.
- Boag SE, Andreano E, Spyridopoulos I. Lymphocyte Communication in Myocardial Ischemia/Reperfusion Injury. Antioxid Redox Signal. 2017; 26(12): 660–675.
- Vignali DAA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012; 13(8): 722–728.
- Wang X, Wei Y, Xiao He, et al. A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice. Eur J Immunol. 2016; 46(6): 1343–1350.
- Takemura G, Fujiwara H. Role of apoptosis in remodeling after myocardial infarction. Pharmacol Ther. 2004; 104(1): 1–16.
- Luo Yu, Liu F, Liu H, et al. Elevated serum IL-39 in patients with ST-segment elevation myocardial infarction was related with left ventricular systolic dysfunction. Biomark Med. 2017; 11(6): 419–426.
- Liao YH, Xia Ni, Zhou SF, et al. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol. 2012; 59(4): 420–429.
- Zhang A, Mao X, Li L, et al. Necrostatin-1 inhibits Hmgb1-IL-23/IL-17 pathway and attenuates cardiac ischemia reperfusion injury. Transpl Int. 2014; 27(10): 1077–1085.
- Qin C, Yap S, Woodman OL. Antioxidants in the prevention of myocardial ischemia/reperfusion injury. Expert Rev Clin Pharmacol. 2009; 2(6): 673–695.
- Prabhu SD, Frangogiannis NG. The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis. Circ Res. 2016; 119(1): 91–112.
- Dewald O, Zymek P, Winkelmann K, et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. 2005; 96(8): 881–889.
- Frangogiannis NG, Dewald O, Xia Y, et al. Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. Circulation. 2007; 115(5): 584–592.
- Liehn EA, Piccinini AM, Koenen RR, et al. A new monocyte chemotactic protein-1/chemokine CC motif ligand-2 competitor limiting neointima formation and myocardial ischemia/reperfusion injury in mice. J Am Coll Cardiol. 2010; 56(22): 1847–1857.
- Du S, Li Z, Xie X, et al. IL-17 stimulates the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation. Scand J Immunol. 2020; 91(1): e12840.
- de Lemos JA, Morrow DA, Sabatine MS, et al. Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation. 2003; 107(5): 690–695.
- Gonzalez-Quesada C, Frangogiannis NG. Monocyte chemoattractant protein-1/CCL2 as a biomarker in acute coronary syndromes. Curr Atheroscler Rep. 2009; 11(2): 131–138.
- Tarzami ST, Calderon TM, Deguzman A, et al. MCP-1/CCL2 protects cardiac myocytes from hypoxia-induced apoptosis by a G(alphai)-independent pathway. Biochem Biophys Res Commun. 2005; 335(4): 1008–1016.
- Hengartner MO. The biochemistry of apoptosis. Nature. 2000; 407(6805): 770–776.
- Ashkenazi A, Fairbrother WJ, Leverson JD, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. 2017; 16(4): 273–284.
- Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517): 727–730.
- Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. 2004; 5(11): 897–907.
- Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002; 298(5600): 1911–1912.
- Zhang W, Liu HTu. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002; 12(1): 9–18.
- Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007; 1773(8): 1358–1375.
- De Chiara G, Marcocci ME, Torcia M, et al. Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences. J Biol Chem. 2006; 281(30): 21353–21361.
- Guo W, Liu X, Li J, et al. Prdx1 alleviates cardiomyocyte apoptosis through ROS-activated MAPK pathway during myocardial ischemia/reperfusion injury. Int J Biol Macromol. 2018; 112: 608–615.
- Kaiser RA, Lyons JM, Duffy JY, et al. Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2005; 289(6): H2747–H2751.
- Shi P, Zhang L, Zhang M, et al. Platelet-Specific p38α Deficiency Improved Cardiac Function After Myocardial Infarction in Mice. Arterioscler Thromb Vasc Biol. 2017; 37(12): e185–e196.
- Molkentin JD, Bugg D, Ghearing N, et al. Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis. Circulation. 2017; 136(6): 549–561.
- Bridgewood C, Alase A, Watad A, et al. The IL-23p19/EBI3 heterodimeric cytokine termed IL-39 remains a theoretical cytokine in man. Inflamm Res. 2019; 68(6): 423–426.
