Cytokines in Sepsis: Potent Immunoregulators and Potential Therapeutic Targets—An Updated View

Table 2

Summary of the main features of pro- and anti-inflammatory cytokines.

Cytokine	Main sources	Main functions	Interactions with other cytokines	Alteration/involvement in diseases	Physiologic inhibitors and therapeutic targeting strategies	References
Proinflammatory
TNF-𝛼	Immune cells of the innate and adaptive immune system (mainly macrophages and lymphocytes); fibroblasts	Differentiation and activation of immune cells; induction of fever and coagulation; cachexia; apoptosis	Promote the release of downstream proinflammatory effector molecules	Role in atherosclerosis, RA, Alzheimer’s disease, autoimmune diseases, and cancer	sTNFRs; anti-TNF Ab; TNFR inhibitors	[35–43]
IL-1	“	Induction of fever and coagulation; hematopoiesis; promotes the extravasation of inflammatory cells	“	Role in autoinflammatory diseases, heart failure, and diabetes	IL-1R2; IL-1Ra; anti-IL-1𝛽 mAb	[16, 38, 39, 44–48]
IL-6	“	Activation of B and T lymphocytes; modulation of hematopoiesis and acute phase response; induction of fever	Released in response to TNF-𝛼 and IL-1 but inhibits their release; promotes anti-inflammatory responses (sTNFRs, IL-1Ra, and TGF-𝛽)	↑ Serum levels following burns, major surgery, in sepsis, RA, and Crohn’s disease	sIL-6R, anti-IL-6 Ab, and anti-IL-6R Ab	[49–63]
IL-12	Monocytes/macrophages; Neutrophils; dendritic cells	Promotes type 1 adaptive immune response and differentiation of TH1 T lymphocytes; induces antitumor immune response	Induces IFN-𝛾 production	Role in cancer	Anti-IL-12 mAb	[64–67]
IFN-𝛾	NK cells; TH1 and CD8^+ cytotoxic T-cells	Antiviral activity; potentially reverses immunoparalysis in sepsis	Released in response to TNF-α, IL-12, and IL-18	↑ Serum levels in sepsis	rIFN-𝛾	[68–73]
MIF	Pituitary cells; monocytes/macrophages	Activation of macrophages and T-cells; overrides the anti-inflammatory effect of glucocorticoids	Released in response to infection, inflammation, and proinflammatory cytokines; promotes the release of proinflammatory effector molecules	↑ Serum levels in acute and chronic inflammatory diseases; role in cancer	Small molecule inhibitors (ISO-1, benzoxazol-2-ones); human anti-MIF Ab; MIF-derived peptide sequences	[69, 74–84]
Anti-inflammatory
IL-10	Immune cells of the innate and adaptive immune system	Immunosuppressive properties, such as the impairment of antigen presentation and phagocytosis	Suppress the release of proinflammatory cytokines; stimulate production of sTNFRs and IL-1Ra	Dysregulated in autoimmune diseases	rIL-10	[85–88]
TGF-𝛽	Macrophages; smooth muscle cells	Involved in tissue repair, fibrosis, and sepsis-induced immunosuppression	“	↑ Serum levels in sepsis; upregulated in cancer and fibrosis	Small molecule inhibitors; anti-TGF-𝛽 mAb	[89–94]
IL-4	TH2 T lymphocytes; mast cells; basophils; eosinophils	Promotes differentiation of TH2 T lymphocytes	Induces release of IL-4 and IL-13 from macrophages	Role in scleroderma, asthma, and tuberculosis	Anti-IL-4R𝛼 mAb	[95, 96]

RA: rheumatoid arthritis; sTNFRs: soluble TNF receptors; mAb: monoclonal antibody; IL-1Ra: IL-1 receptor antagonist; rIFN-𝛾: recombinant IFN-𝛾; ISO-1: (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester.