Role of interleukins in the pathogenesis of coronary heart disease: A literature review

Table 1 Origin/source, functions, and pathophysiological aspects of interleukins in coronary heart disease

Interleukins	Origin/source	Functions	Pathophysiological aspects	Ref.
IL-1	Monocytes, macrophages, lymphocytes, neutrophils, fibroblasts	Lymphocyte activation, fever, regulates sleep, pro-inflammatory cytokine, maturation and proliferation	It has been shown that chronic administration of IL-1β to the myocardial and coronary arteries causes cardiac dysfunction and coronary arteriosclerosis. Pericardial IL-1β concentrations could indicate the degree of ischemic heart disease, and high levels of IL-1β in pericardial fluid might also directly encourage the development of coronary atherosclerosis. It was shown that the adventitial vessel walls of atherosclerotic coronary arteries had higher levels of IL-1β protein than coronary arteries from non-ischemic cardiomyopathic hearts. This rise correlated directly with the degree of coronary atherosclerosis	[13,14]
IL-2	Th1 cells	Stimulates growth of T cells	Not determined
IL-3	Th cells and mast cells	Stimulates bone marrow growth	Patients with CAD, especially those who are symptomatic and receiving percutaneous coronary intervention, have higher levels of IL-3, a key regulator of chronic inflammation. Moreover, a correlation between symptomatic restenosis and elevated IL-3 concentrations was discovered	[23]
IL-4	Th2 cells, basophils, NKT cells	B-cell growth factor, role in tissue adhesion and inflammation	Serum IL-4 levels are reliable indicators of CAD	[19]
IL-5	T cells	Activated T cells, Differentiation and function of myeloid cells	In the coronary plaque of CAD patients, IL-5 was substantially lower than in the group of deceased donors. The coronary artery plaque’s macrophages were the primary source of IL-5. Stable angina pectoris, unstable angina pectoris, and acute myocardial infarction were the sequences from high to low plasma IL-5 levels in the CAD groups, which were considerably lower than those in the non-CAD group. The results of binary linear regression analysis indicated an independent correlation between IL-5 and the incidence of CAD. Th1 and Th17 levels and the mRNA expression of their distinctive cytokines were reduced in CD4+Th cells treated with oxidized low-density lipoprotein after being treated with recombinant mouse IL-5. Near the IL-5 locus, genetic polymorphisms were shown to be strongly linked to coronary artery disease	[25,29]
IL-6	Monocytes, macrophages,	Activated T cells, contributes to host defense through the stimulation of acute phase responses, hematopoiesis	IL-6 helps serve as a reliable biomarker for the degree of CAD as determined by the Gensini score and it is a key factor in the development of atherosclerosis. IL-6 may be a useful marker for assessing the degree of necrosis	[31]
IL-7	Monocytes, macrophages, epithelial cells	T-cell development, survival and homeostasis of mature T cells, B cells and T-cell proliferation	One important factor contributing to the elevated IL-7 levels in angina patients seems to be increased release from activated platelets. Based on interactions between platelets, monocytes, and chemokines, the data point to a role for IL-7-driven inflammation in atherogenesis and the enhancement of clinical instability in CAD	[39]
IL-8	Monocytes and fibroblasts	Angiogenesis, induces chemotaxis, stimulates phagocytosis, neutrophil chemotaxis, superoxide release and granule release	The expression of IL-8 mRNA or plasma IL-8 showed a strong negative connection with the development of CHD. IL-8 plays a part in the progression of CAD occurrences	[42,44]
IL-9	Eosinophils, mast cells	Chemokine, Mast and T-cell growth factor and enhances T-cell survival, mast cell activation and synergy with erythropoietin	IL-9 may interact with established CAD risk factors to cause CAD	[48]
IL-10	Macrophages, T cells, B cells, dendritic cells	Immune suppressed	IL-10 indicates a proinflammatory state in acute coronary syndrome patients. As a result, IL-10 is a biomarker as useful as other systemic inflammation markers for predicting the risk of future cardiovascular events	[53]

CAD: Coronary artery disease; CHD: Coronary heart disease; IL: Interleukin; NKT: Natural killer T; Th1: Type 1 T helper cell.

Table 2 Overall summary of therapeutic strategies in coronary heart disease

Interleukins	Summary of therapeutic strategies	Ref.
IL-1	It suggested that IL-1 and associated cytokines could be therapeutic targets for both stable and unstable CAD. Statins' capacity to alter this system in an anti-inflammatory manner emphasizes their potential for immunomodulation. Commonly used medicinal compounds or specific molecules with focused anti-inflammatory effects can target these molecules. Together with newer treatments like TNF-α inhibitors and IL-1 receptor antagonists, the most important anti-inflammatory medications include aspirin, statins, colchicine, IL-1β inhibitors, and IL-6 inhibitors. Because of their pleiotropic and anti-inflammatory properties, aspirin and statins are well-established treatments for atherosclerosis and CAD. Identifying patients with high inflammatory profiles (e.g., elevated IL-1β or hsCRP levels) could help tailor anti-inflammatory interventions. Investigating the roles of IL-1α and IL-1 receptor antagonists in CHD could further refine therapeutic strategies	[18,73]
IL-2	Immune tolerance is induced and immunological homeostasis is maintained by regulatory T cells. Low-dose IL-2 may be able to boost the number of Treg cells, according to recent in vivo research. Human recombinant IL-2, known as aldesleukin, has been utilized therapeutically to treat several autoimmune disorders. For individuals with ischemic heart disease, larger studies are required to verify the safety and assess the effectiveness of low-dose IL-2 as an anti-inflammatory treatment	[21,22]
IL-3	Not determined
IL-4	Not determined
IL-5	The atheroprotective effects of IL-5 in atherosclerosis have been demonstrated to include promoting B-1 cell differentiation to release more T15/EO6 antibodies, which can inhibit macrophage absorption of oxidized low-density lipoprotein and decrease the production of foam cells. Understanding its complex contributions to immune and vascular processes could lead to new insights and therapeutic strategies for reducing CHD risk and improving cardiovascular outcomes	[27]
IL-6	It revealed that although the IL-6 signaling cascade and the anti-inflammatory effect of HMG-CoA reductase were found to influence the risk of CAD. The anti-CAD effect of statins may rely on inflammatory pathways other than the IL-6 signaling cascade. The authors examined the effectiveness and current uncertainties of colchicine, IL-6 receptor antagonists, and IL-1β antibodies in the anti-inflammatory management of coronary atherosclerotic heart disease. Previous studies have indicated that rosuvastatin inhibits c-Jun N-terminal kinase and NF-κB to reduce the inflammatory response. Additionally, adhesion molecules and some cytokines, including IL-8, IL-6, and MCP-1, have been discovered to be decreased by it	[32,73,66]
IL-7	Aspirin was given to healthy control volunteers for seven days at a dose of 160 mg per day, and it decreased the levels of IL-7 in their plasma. It also decreased the release of IL-7 from platelets both spontaneously and in response to SFLLRN stimulation. Blocking IL-7 or its IL-7R may reduce T-cell-mediated inflammation and slow atherosclerosis progression. IL-7R inhibitors are under investigation for autoimmune diseases and could be repurposed for CHD	[39]
IL-8	Patients with CHD who had been taking statins continuously showed a substantial reduction in both transcriptomic and phenotypic IL-8 expression when compared to the H and N group individuals. Consequently, IL-8 need to function as a practical marker and be employed to assess the therapeutic benefits of statins as well as to depict the pathophysiology of CHD therapy. Coronary atherosclerotic plaques are reduced, vascular inflammation is reduced, and bad cholesterol is decreased as a result of atorvastatin and rosuvastatin's therapeutic actions. In this meta-analysis research, intravascular ultrasound imaging showed that both medications may regress the composition of atherosclerotic plaques, raise the coronary artery lumen volume, and dramatically reduce atheroma volume. The rupture that results in vascular occlusion is avoided by the regression and stability of plaque. Blocking IL-8 or its receptors (CXCR1 and CXCR2) may reduce vascular inflammation, immune cell recruitment, and plaque progression. CXCR2 inhibitors are being explored for other inflammatory diseases and may have potential for CHD	[42,71]
IL-9	IL-9 may contribute to the development of CAD and offer an innovative approach to its prevention and management. Blocking IL-9 or its IL-9R may help mitigate vascular inflammation and atherosclerosis progression	[48]
IL-10	Therapeutic approaches that enhance IL-10 activity or mimic its effects hold promise for preventing and treating CHD. IL-10 levels might serve as a biomarker for anti-inflammatory activity and cardiovascular risk stratification	[51-57]

CAD: Coronary artery disease; CHD: Coronary heart disease; CRP: C-reactive protein; CXCR1: C-X-C motif chemokine receptor 1; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; hsCRP: High-sensitivity C-reactive protein; IL: Interleukin; MCP-1: Monocyte chemoattractant protein-1; NF-kB: Nuclear factor kappa B; TNF-a: Tumor necrosis factor alpha.