From joints to vessels: How rheumatoid arthritis therapy alters the fate of the heart

Table 2 Role of cytokines in the pathogenesis of rheumatoid arthritis and cardiovascular disease

Cytokine	Major sources	Effects in RA	Effects in CVD	Common pathogenic effects
TNF-α	Macrophages, Th1 cells, adipocytes	Activates synovial fibroblasts	Endothelial dysfunction	NF-κB activation
		Stimulates osteoclasts (via RANKL)	Increased leukocyte adhesion	Induction of cellular apoptosis
		Induces MMP-9 production	Atherosclerotic plaque destabilization	Stimulation of IL-6 production
IL-6	Macrophages, Th1 cells, adipocytes	Stimulates B-cells (RF production)	Enhances fibrinogen synthesis	JAK/STAT pathway activation
		Induces acute-phase proteins (CRP, SAA)	Promotes cardiomyocyte hypertrophy	Induction of insulin resistance
		Causes anemia of chronic disease	Accelerates atherogenesis
IL-1β	Macrophages, neutrophils	Stimulates chondrocyte protease production	Increases platelet aggregation	NLRP3 inflammasome activation
		Induces fever and pain	Upregulates adhesion molecules (VCAM-1)	Angiogenesis stimulation
		Activates osteoclasts	Plaque destabilization
IL-17	Th17 cells, γδT cells	Promotes synovial neoangiogenesis	Increases endothelial ET-1 production	MAPK pathway activation
		Induces neutrophil infiltration	Promotes myocardial fibrosis	Stimulates IL-6 production
		Synergizes with TNF-α	Enhances oxidative stress
IL-10	Tregs, B-cells, macrophages	Suppresses TNF-α and IL-6 production	Stabilizes atherosclerotic plaques	NF-κB inhibition
		Inhibits Th17 activation	Reduces leukocyte adhesion	SOCS3 stimulation
IFN-γ	Th1, natural killer cells	Activates synovial macrophages	Increases plaque vulnerability	STAT1 activation
		Inhibits Th17 differentiation	Stimulates smooth muscle cell apoptosis	Enhances MHC II expression

TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; IL-1β: Interleukin-1β; IL-17: Interleukin-17; IL-10: Interleukin-10; IFN-γ: Interferon-gamma; T-helper 1/17: Lymphocyte subsets (Th1; Th17); γδT: Gamma-delta T cells; Tregs: Regulatory T cells; RANKL: Receptor activator of nuclear factor kappa-B ligand; MMP: Matrix metalloproteinase; VCAM-1: Vascular cell adhesion molecule-1; ET-1: Endothelin-1; MHC II: Major histocompatibility complex class II; CRP: C-reactive protein; SAA: Serum amyloid A; CVD: Cardiovascular disease; RA: Rheumatoid arthritis.