Research Progress and Functional Overview of Interleukins-ExKits

Research Progress and Functional Overview of Interleukins

Interleukins represent a major category of cytokines, exerting core regulatory effects on immune balance and inflammatory responses. Initially identified in leukocytes, these bioactive molecules are now confirmed to be synthesized and secreted by multiple cell types, including macrophages and lymphocytes with complete structural integrity and biological functions. This review systematically summarizes key information related to interleukins, covering family classification and receptor distribution, classic signaling cascades, biological functions, as well as their regulatory roles in various inflammatory disorders.

Interleukin Family and Interleukin Receptors

The interleukin superfamily contains abundant members, sequentially named from IL-1 to IL-38.

Interleukin receptors are mainly divided into three categories: type I, type II and atypical receptors. Type II receptors primarily correspond to IL-10, IL-20, IL-22 and IL-28; atypical receptors mainly include IL-1 and IL-8 receptors; and the remaining interleukin receptors all belong to the type I category.

Table 1. Interleukin Family and Receptors

Gene Name/Alias	Uniprot ID	Protein Name	Receptors
IL-1 α	P01583	Interleukin-1 alpha	IL1R1, IL1R2
IL-1 β	P01584	Interleukin-1 beta	IL1R1, IL1R2
IL-2	P60568	Interleukin-2	IL2RA, IL2RB, IL2RG
IL-3	P08700	Interleukin-3	IL3RA, IL3RB
IL-4	P05113	Interleukin-4	IL4R
IL-5	P05113	Interleukin-5	IL5RA, IL3RB
IL-6	P05231	Interleukin-6	IL6R
IL-7	P13232	Interleukin-7	IL7R
IL-8 /CXCL8	P10145	Interleukin-8	IL-8, IL8RB
IL-9	P15244	Interleukin-9	IL9R
IL-10	P22301	Interleukin-10	IL10RA
IL-11	P20809	Interleukin-11	IL11RA
IL-12 α	P29459	Interleukin-12 subunit alpha	IL12RB1
IL-13	P35225	Interleukin-13	IL13RA1, IL13RA2
IL-14/TXLNA	P40222	Alpha-taxilin	Unknown
IL-15	P40933	Interleukin-15	IL15RA
IL-16	Q14005	Pro-interleukin-16	CD4
IL-17 α	Q16552	Interleukin-17A	IL17RA
IL-18	Q14116	Interleukin-18	IL18R1
IL-19	Q9UHD0	Interleukin-19	IL20R
IL-20	Q9NYY1	Interleukin-20	IL20R
IL-21	Q9HBE4	Interleukin-21	IL21R
IL-22	Q9GZX6	Interleukin-22	IL22RA1
IL-23	Q9NPF7	Interleukin-23 subunit alpha	IL23R
IL-24	Q13007	Interleukin-24	IL20R
IL-25	Q9H293	Interleukin-25	LY6E
IL-26	Q9NHP9	Interleukin-26	IL20R1
IL-27 α	Q8NEV9	Interleukin-27 subunit alpha	IL27RA
IL-27 β	Q14213	Interleukin-27 subunit beta	IL27RA
IL-28	Q8IU57	Interferon lambda receptor 1	IL28R
IL-29/IFNL1	Q8IU54	Interferon lambda-1	Unknown
IL-30	Q8NEV9	Interleukin-27 subunit alpha	Unknown
IL-31	Q6EBC2	Interleukin-31	IL31RA
IL-32	P24001	Interleukin-32	Unknown
IL-33	O95760	Interleukin-33	Unknown
IL-35	Q14213	Consist of IL-12α and IL-27β chains	Unknown
IL-36 α	Q9UHA7	Interleukin-36 alpha	Unknown
IL-36 β	Q9NZH7	Interleukin-36 beta	Unknown
IL-36 γ	Q9NZH8	Interleukin-36 gamma	Unknown

Common Signaling Pathway

This section focuses on several representative interleukin signaling cascades, including IL-1, IL-10, IL-12, IL-17 and IL-7 related regulatory pathways.

IL-1 Signaling Pathway

The IL-1 family contains 11 distinct members. Typical members such as IL-1, IL-18, IL-33 and IL-36 bind specifically to corresponding primary membrane receptors. Activation of IL-1α, IL-1β, IL-18, IL-33 and multiple IL-36 isoforms can trigger downstream MAPKK and NF-κB cascades, ultimately driving inflammatory reactions. Conversely, several other members of the IL-1 family exert anti-inflammatory biological effects. As a core pro-inflammatory cytokine, IL-1 participates in the co-stimulation of helper T cells, promotes the maturation and proliferation of B lymphocytes, activates NK cells, and serves as a key regulatory factor in the occurrence and development of inflammation.

The image of IL-1 signaling pathway

Fig.1. The image of IL-1 signaling pathway

IL-10 Pathway

IL-10 is a classic anti-inflammatory cytokine, mainly secreted by activated T lymphocytes, B cells, macrophages and mononuclear cells. It can regulate the cytokine secretion profile of macrophages, promote the activation of B cells and the differentiation of Th2 cells, while effectively suppressing the activation and cytokine release of Th1 cells. Endogenous IL-10 exists in the form of homodimer, which binds to the tetrameric heterodimeric IL-10 receptor complex, thereby blocking the transduction of IL-6, TNF and other pro-inflammatory signaling pathways. Current studies have confirmed that IL-10 is closely associated with the progression of non-small cell lung cancer.

The image of IL-10 signaling pathway

Fig.2. The image of IL-10 signaling pathway

IL-12 Pathway

The IL-12 family consists of four major members. As a branch of the IL-6 superfamily, IL-12, IL-25, IL-27 and IL-35 are unique heterodimeric cytokines. They activate the JAK/STAT signaling axis and induce the phosphorylation modification of STAT1/3/4 proteins to exert biological functions. IL-12 is essential for initiating and maintaining Th1-type cellular immunity, assisting the host in resisting invasion and infection by various intracellular pathogens.

The image of IL-12 signaling pathway

Fig.3. The image of IL-12 signaling pathway

IL-17 Pathway

The IL-17 family includes 6 ligands and 5 corresponding receptors, playing an indispensable role in innate and adaptive immune regulation. IL-17A is the signature molecule of this family, which defends the host against extracellular microbial infections and mediates excessive inflammatory damage in multiple autoimmune diseases; IL-17C shares similar biological properties with IL-17A. IL-17F mainly participates in mucosal immune defense, while IL-17E enhances Th2-type immune responses. The IL-17 family can activate downstream MAPK, NF-κB and C/EBPs signaling axes to induce the expression of antibacterial cytokines and chemokines, and the adaptor protein Act1 is recognized as the core transduction mediator in this pathway.

The image of IL-17 signaling pathway

Fig.4. The image of IL-17 signaling pathway

IL-7 Pathway

IL-7 is a 25 kDa glycoprotein predominantly secreted by bone marrow stromal cells, which is vital for the development and maturation of the immune system, though its specific regulatory mechanisms remain to be further explored. A landmark study revealed that IL-7 can inhibit the expression of Socs3, a key negative regulator of cytokine signaling, thereby enhancing the secretion of multiple cytokines, expanding effector T cell populations and accelerating virus clearance. The relevant research outcomes were published in the journal Cell in 2011.

Interleukin Function

Interleukins act as critical signaling molecules in the immune system, responsible for information transmission, immune cell activation and functional regulation, and mediate the proliferation, differentiation and activation of T cells and B cells.

IL-1 contains two main subtypes: IL-1α and IL-1β. IL-1α is widely expressed in various cell types, while IL-1β is synthesized and secreted in specific tissues. Mature IL-1β is generated via cleavage by caspase-1, and caspase-1 activation relies on the assembly of intracellular inflammasome complexes. IL-1 can induce pain response and short-term sleep changes, which provides a new direction for exploring the correlation between inflammatory factors and physical fatigue. In addition, IL-1 can stimulate the production of nitric oxide, chemokines and adhesion molecules, triggering cartilage tissue damage; whereas the IL-1 receptor antagonist can competitively bind to the same receptor to block IL-1 mediated pathological damage. These research findings help to clarify the pathological mechanism of chronic inflammatory joint diseases.

Over the past 36 years, IL-2 has always been a research hotspot, with broad application prospects in the immunotherapy of malignant tumors and other diseases. However, high-dose IL-2 treatment often brings obvious adverse reactions. Therefore, optimizing the administration cycle and matching the functional status of T cells are the key to improving the safety and efficacy of IL-2 targeted therapy.

As a key anti-inflammatory mediator, IL-10 balances excessive immune activation by regulating the functional status of T cells and antigen-presenting cells. Targeted regulation of IL-10 receptor activity has been proven to effectively improve chronic persistent viral infection.

IL-18 is a multifunctional regulatory factor involved in tumor immune escape and autoimmune disease progression. As a member of the IL-1 family, it participates in the whole process of inflammatory response. It synergizes with IL-12 to activate cytotoxic T cells and NK cells, induce IFN-γ secretion and enhance anti-tumor immunity. Meanwhile, it can cooperate with IL-23 to promote IL-17 release, showing dual regulatory effects in the treatment of various inflammatory and tumor diseases.

Interleukin and Inflammation

Inflammation is a defensive physiological response of the body against pathogenic infection and tissue damage, characterized by typical symptoms including redness, swelling, heat, pain and organ dysfunction, and often accompanied by fever in severe cases. Inflammasome assembly and activation can initiate caspase-1 cleavage, further promoting the maturation and release of pro-inflammatory factors such as IL-1β and IL-18, and inducing cell pyroptosis. Moderate inflammation helps the body eliminate harmful stimuli, while persistent chronic inflammation will lead to autoimmune lesions and tissue damage, such as rheumatoid arthritis.

Interleukin-17 and Psoriasis

Psoriasis is a common chronic inflammatory skin disease, characterized by erythema and scaly skin lesions, and closely associated with cardiovascular complications such as atherosclerosis. Immune system disorder is the core pathogenesis of psoriasis, and a large number of inflammatory mediators including TNF, IFN, IL-1β, IL-6, IL-12, IL-17, IL-22 and IL-23 are highly expressed in lesion tissues. Clinical samples confirmed that the proportion of Th17 cells and the expression levels of IL-17A were significantly increased in psoriasis patients.

Interleukin and Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a refractory autoimmune disorder, which can cause progressive cartilage erosion, joint structural destruction and long-term poor prognosis. Genetic polymorphism of inflammatory related genes is an important susceptible factor for RA. Caspase-1 acts as a key pathogenic mediator, and knockout of caspase-1 can significantly relieve RA inflammatory symptoms.

Interleukin and Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease, which attacks normal tissues and organs throughout the body, leading to multiple clinical manifestations including inflammatory arthritis, renal injury, oral ulcer and typical butterfly erythema. Lupus nephritis is the most severe complication of SLE, and often causes irreversible renal damage.

Interleukin and Crohn's Disease

Crohn's disease (CD) is an incurable chronic inflammatory disease of the gastrointestinal tract. At present, targeted biological agents against TNF, IL-12/IL-23 p40 subunit are widely used in clinical treatment. IL-6 is a vital pro-inflammatory factor in intestinal inflammation, which can inhibit T lymphocyte apoptosis and become a new therapeutic target for CD.

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