Interleukins in liver disease treatment

Table 1 Interleukin families in liver diseases

IL family	Members	Functions
IL-1	IL-1α, IL-1β, IL-18, IL-33, IL-36, IL-37, and IL-38	Mediate inflammatory responses to a wide range of stimuli in both innate and adaptive immune systems, with pro- and anti-inflammatory functions[12,13]
IL-2	IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21	Regulate T cell proliferation and activation, NK cytolytic activity, and the differentiation of regulatory T cells[14,15]
IL-6	IL-6, IL-11, IL-27, IL-31, oncostatin M, leukemia inhibitory factor, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1s	Play important roles in B-cell stimulation, the balance between regulatory and effector T cells, metabolic regulation, hepatic acute phase reaction, and many neural functions[16,17]
IL-8	IL-8, also known as CXCL8	It is a member of the chemokines, which has biological functions on cells expressing CXCR1 and CXCR2 receptors, such as polymorphonuclear leukocytes (neutrophils), epithelial cells, endothelial cells, fibroblasts, and neurons[18,19]
IL-10	IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26	Display immunosuppressive functions, elicit innate defense mechanisms against viral, bacterial, and fungal infections, promote tissue repair and regeneration, and provide therapeutic targets for autoimmune diseases and cancers[20,21]
IL-12	IL-12, IL-23, IL-27 and IL-35	Regulate immune responses and influence naïve T cell differentiation in many inflammatory diseases, autoimmune diseases, and various cardiovascular diseases[22,23]
IL-17	IL-17A to IL-17F (IL-17E also known as IL-25)	Defense against microbial (bacteria, fungi, and helminth) infection, recruit neutrophils, and modify T-helper cell differentiation[24,25]

IL: Interleukins.

Table 2 Interleukins and their receptors

Interleukin	Type 1 receptors	Interleukin	Type 2 receptors	IL-1 family member	Receptor
IL-2	IL-2Rα, IL-2Rβ, IL-2Rγ	IL-10	IL-10Rα, IL-10Rβ	IL-1α, IL-1β	IL-1R1, IL-1R3
IL-3	IL-3Rα, CSF2Rβ	IL-19, IL-20, IL-24	IL-20Rα, IL-20Rβ	IL-1β	IL-1R2, IL-1R3
IL-4	IL-4R, IL-2Rγ/IL-13Rα1	IL-22	IL-22Rα1, IL-10Rβ	IL-1Rα	IL-1R
IL-5	IL-5Rα, CSF2Rβ	IL-20, IL-24	IL-22Rα1, IL-20Rβ	IL-18	IL-1R5, IL-1R7
IL-6	IL-6Rα, gp130	IL-26	IL-10Rβ, IL-20Rα	IL-33	IL-1R4, IL-1R3
IL-7	IL-7Rα, IL-2Rγ	IL-28, IL-29	IL-28Rα, IL-10Rβ	IL-36	IL-1R6, IL-1R3
IL-9	IL-9R, IL-2Rγ			IL-37	IL-1R5, IL-1R8
IL-11	IL-11Rα, gp130			IL-38	IL-1R6, IL-1R9
IL-12	IL-12Rβ1, IL-12Rβ2
IL-13	IL-13Rα1, IL-13Rα2, IL-4R
IL-15	IL-15Rα, IL-2Rβ, IL-2Rγ
IL-16	CD4, CD9
IL-21	IL-21R, IL-2Rγ
IL-23	IL-12Rβ1, IL-23R
IL-27	IL-27Rα, gp130
IL-31	IL-31Rα, OSMR
IL-34	CSF-1R
IL-35	IL-12Rβ2, gp130

IL: Interleukins.

Table 3 Interleukin-mediated therapies in liver disease

Clinical trials	Phase	Liver disease	Interleukin therapy
NCT00565539	1	Chronic hepatitis C virus (HCV) infection	PEGylated recombinant interleukin 29 (PEG-rIL-29) or in combination with daily oral ribavirin (an antiviral drug)
NCT03882307	1	Hepatitis C virus (HCV) infection	Test the association of serum levels of IL-6 and TGF-β in response to antiviral therapy (sofosbuvir and daclatasvir) for chronic hepatitis C patients
NCT02431312	1	Chronic hepatitis B	Evaluate the safety, tolerability, and immunogenicity of dose combinations of INO-1800 (DNA plasmids encoding hepatitis B surface antigen and hepatitis B core antigen) and INO-9112 (DNA plasmid encoding human interleukin 12) delivered by electroporation
NCT02655510	1/2	Alcoholic hepatitis	To test the efficacy of F-652, a recombinant fusion protein containing human IL-22 and human immunoglobulin G2 (IgG2)-Fc produced in CHO cells in serum-free culture
NCT03775109	2	Alcoholic hepatitis	To evaluate the potential benefits of the IL-1β antibody Canakinumab in the treatment of alcoholic hepatitis
NCT01988506	2	Autoimmune hepatitis, and other autoimmune and auto-inflammatory diseases	Low-dose IL-2 to induce regulatory T cells
NCT00196586	2	Chronic hepatitis C	Evaluate the efficacy and safety of the addition of IL-2 to pegylated interferon α-2a and ribavirin in patients with HCV/HIV coinfection
NCT01697501	3	Chronic hepatitis B	Evaluating the IL-28B polymorphism in patients with HBeAg-negative chronic hepatitis B treated with pegylated interferon α-2a
NCT03090035	3	Chronic hepatitis C	Test IL-28B (rs12979860) genotypes in patients with chronic hepatitis C infection treated with pegylated interferon α2 plus ribavirin
NCT02360592	4	Chronic hepatitis B	Evaluate the efficacy and safety of interferon α-2b therapy plus IL-2 and hepatitis B therapeutic vaccine compared to interferon α-2b alone
NCT03734783	Observational	Chronic hepatitis B	Investigate the levels of IL-35-secreting B regulatory cells in peripheral blood cells in patients with chronic hepatitis B and their functions on Th1 and Th2 cell levels

IL: Interleukins.