Introduction to the Function of Interleukins

What Are Interleukins?

Interleukins (IL) are produced by lymphocytes and monocytes and bind to specific receptors on other inflammatory cells and the immune system (B-cells, T-cells, mast cells) to produce a transient response. Macrophages and endothelial cells synthesize interleukins along with tumor necrosis factor (TNF), which also gives the two cytokines the same functional properties and similar behavior. After bacterial invasion, macrophages recognize the outsiders, are activated and secrete IL-1 and TNF. These hormones alter the lining of blood vessels, activate T cells, and circulate to the brain. IL-1 and TNF in the brain promote the synthesis of prostaglandin E2, which alters our internal regulation of body temperature.

CD4⁺ Th cells can be categorized into different subpopulations based on different cytokine profiles, and the cytokine expression profiles depend on the adjuvanticity of the molecules presented with the antigen and the status of the T cells, as well as the type of antigen-presenting cells (APCs) and cytokines in the microenvironment. Different interleukins can interact with specific Th cells to promote different types of inflammatory responses. For example, effector Th2 cells produce IL-4, IL-5, IL-9, and IL-13 in allergic diseases, and their production of IL-25, IL-31, and IL-33 promotes TH2 responses and inflammation. TH17 cells express IL-6, IL-8, IL-22, and IL-26.

Figure 1. Antigen presentation by DCs to naive T cells induces the T cells to produce ILs and differentiate into TH1, TH2, TH9, TH17, TH22, or follicular TH (TFH) cells
（Source: Akdis M, et al. 2011）

IL-1 Family

Interleukin 1

IL-1, originally known as the human leukocyte pyrogen, consists of IL-1α and IL-1β, which share similar, albeit minimal, sequence homology but have similar biological properties, although they differ fundamentally in their localization, maturation, and secretion. IL-1α is translated into a biologically active form, whereas IL-1β is translated into pro-IL-1β, which is biologically inactive until processed by caspase-1. IL-1α and IL-1β exert similar effects by binding to the IL-1 type I receptor (IL-1RI).

IL-1β is a circulating factor whose expression is tightly regulated. The main source of IL-1β is myeloid cells, which express the cytokine as a cytoplasmic 31kDa precursor protein (pro-IL-1β) that needs to be converted to the mature form to function. IL-1β is usually activated by caspase-1 cleavage of the N-terminal precursor region of pro-IL-1β. Different lysis sites for neutrophil protease and mast cell chymotrypsin are present in the N-terminal region of pro-IL-1β, and thus these proteases can independently produce mature and active IL-1β. Due to the absence of a pilot sequence, mature IL-1β is released in the environment through an unconventional secretory mechanism independent of the endoplasmic reticulum and Golgi network.

Figure 2. The two-step paradigm of controlled IL-1β release
(Source: Van Den Eeckhout B, et al. 2021)

IL-1 is a potent pro-inflammatory cytokine with multiple potentiating effects on cell proliferation, differentiation and function of many innate and specific immune cells. IL-1 mediates many inflammatory diseases by initiating and enhancing immune and inflammatory responses. There are currently 21 members of the IL-1 superfamily of ligands and receptors, including 11 soluble factors and 10 receptor molecules. Of these soluble factors, seven are pro-inflammatory and four are anti-inflammatory. Two of these anti-inflammatory mediators are receptor agonists and two are receptor antagonists. The IL-1 receptor superfamily is divided into several subgroups: ligand-binding receptor proteins, accessory chains, molecules that inhibit signaling, and orphan receptors.

Interleukin 18

IL-18, a member of the IL-1 family, is expressed by macrophages, Kupffer cells, keratinocytes, dendritic cells and a series of cells. It shares the same structural features as IL-1 and also requires caspase-1 lysis to become a biologically active molecule. IL-18 binds to IL-12 to induce T cells to produce high levels of IFN-γ, whose biological activity can be neutralized by IL-18-binding proteins. IL-18 expression has been associated with rheumatoid arthritis and Crohn's disease activity.

ILs with Chemokine Activity

Interleukin 8

IL-8 was identified as a neutrophil-specific chemokine and later classified as a member of the CXC chemokine family. A variety of cells can produce IL-8 upon stimulation with IL-1-α, IL-1-β, IL-17, TNF-α, or TLRs, including monocytes, macrophages, neutrophils, lymphocytes, endothelial cells, and epithelial cells. IL-8 production is dependent on upstream NF-κB signaling, while chemokines themselves trigger downstream activation of PI3K and MAPK signaling cascades. The primary function of IL-8 is to bind to two G protein-coupled receptors, CXCR1 and CXCR2, and is responsible for the activation and recruitment of neutrophils to sites of infection or injury. In addition to neutrophils, IL-8 attracts NK cells, T cells, basophils and GM-CSF-catalyzed or IL-3-catalyzed eosinophils. IL-8 concentrations are elevated at sites of inflammation in patients with rheumatoid arthritis, respiratory syncytial virus infection, or chronic obstructive pulmonary disease (COPD).

In the tumor context, IL-8 has a dual pro-tumorigenic effect, on the one hand directly affecting the tumor cells themselves and on the other hand altering the composition of the tumor microenvironment. In addition, elevated IL-8 has been shown to be associated with poor prognosis in many cancers and the development of resistance to therapy. Peripheral blood levels of IL-8 can serve as a prognostic marker for patients receiving chemotherapy or more targeted drug therapy for many tumor types, and many preclinical studies have demonstrated that IL-8 plays a direct role in driving resistance mechanisms to chemotherapy, molecularly targeted therapies, and immune checkpoint inhibition therapies.

Figure 4. The role of IL-8 in various aspects of tumor progression
(Source: Fousek K, et al. 2021)

IL ELISA Kits

IL Antigens

IL Antibodies