Chart 1.
Inflammatory cytokines and their effects on renal function in diabetes mellitus
| Cytokines | Stimulated by | Specialized producing cells | Exerts positive effects on | Effects on DKD | Target cells in the kidneys | Ref. |
|---|---|---|---|---|---|---|
| IL-1α, IL-1β |
Inflammasome IL-18 and NF-κB |
Macrophages, Granulocytes* Tubular epithelial Endothelial, Mesangial† Fibroblasts‡ |
↑ ICAM-1, ↑ VCAM-1, ↑ Prostaglandin E2 | ↑ Intraglomerular hemodynamic abnormality,
↑ Synthesis of hyaluronic acid, ↑ Proliferation of mesangial cells and fibroblasts, ↑ECM accumulation |
Epithelial, Mesangial, Tubular | [77, 83] |
| IL-6 | Hyperglycemia, AGEs, TNF-α, LPS, IL-1, IL-4 | T lymphocytes, Macrophages, Neutrophils* Endothelial, Podocytes, Mesangial, Tubular epithelial† Fibroblasts‡ |
↑ MCP-1, ↑ expression of Ang II receptors, ↑ ROS | ↑ Recruitment of monocytes, ↑ Differentiation of macrophages, ↑ Synthesis of fibronectin, ↑ Synthesis and accumulation of ECM, ↑ Mesangial cell proliferation, ↑ Endothelial dysfunction ↑ Tubulointerstitial fibrosis | Mesangial, Podocytes, Endothelial, Tubular epithelial | [84, 85] |
| IL-18 | NF-κB, Inflammasome, Caspase-1 | T lymphocytes and Macrophages* Epithelial, Tubular† |
↑ IFN-γ, ↑ IL-1, IL-6, TNF-α, iNOS, ICAM-1, TGF-β, MCP-1 | ↑ Apoptosis of endothelial cells, ↑ infiltration off macrophages and neutrophils | Endothelial, Tubular epithelial | [30, 86, 87] |
| TNF-α | NF-κB | Dendritic, Monocytes, Macrophages,
Tlymphocytes* Mesangial, Endothelial, Tubular† |
↑ Immune response ↑ NF-κB | ↑ Inflammatory cells, cell infiltration ↑ Citotoxicity, apoptosis, ↑ Endothelial permeability, ↓ Capillary wall barrier function, ↑ PKC, ↑NOX, ↑ ROS; ↑ ECM | Mesangial, Podocytes, Endothelial, Glomerular; Tubular epithelial | [19, 78, 83] |
*
Infiltrating immune cells;
†
Renal cells;
‡
Other cell types. Ang II: angiotensin 2; ROS: reactive oxygen species; TNF-a: tumor necrosis factors alfa; NF-κB: nuclear factor-kappa B; IFN-γ: interferon gamma; IL-1: interleukin 1; IL-1a: interleukin 1 alpha; IL-1b: interleukin 1 beta; IL-6: interleukin 6; IL-18: interleukin 18; IL-4:interleukin 4; LPS: lipopolysaccharide; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule; ECM: extracellular matrix; NOX: NADPH oxidase; AGE: advanced glycation end-products; MCP-1: monocyte chemoattractant protein; PKC: protein kinase C; iNOS: nitric oxide synthase; TGF-b: transforming growth factor-beta