Interleukin-6 (IL-6) Family

Introduction to the IL-6 Family

The Interleukin-6 family (IL-6 family) is a significant cytokine family comprising members such as IL-6, IL-11, IL-27, IL-31, LIF, and CNTF. These members of the IL-6 family play crucial roles in physiological processes including immune regulation, inflammatory responses, and cell proliferation and differentiation.

The Discovery Process of the IL-6 Family

In the 1970s, IL-6 was initially identified by Kishimoto's group as a soluble protein produced by T cells, capable of stimulating B cells to differentiate into antibody-producing cells. As a result, it was initially named B cell stimulating factor 2 (BSF-2).
In 1986, researchers discovered IFN-β2 and a 26-kD protein in fibroblasts that were found to be identical to BSF-2. That same year, the cDNA of the human BSF-2 gene was successfully cloned.
In 1987, the hepatocyte-stimulating factor and plasmacytoma growth factor were also cloned and found to be IL-6, confirming multiple biological activities of the protein.
The molecule was officially designated as IL-6 in 1988 during a conference titled "Acute Phase and Regulation of the Immune Response: A Novel Cytokine."

Physical and Chemical Properties

IL-6 is a small glycoprotein with a molecular weight ranging from 19 to 28 kDa. It is composed of 184 amino acids that form four α-helical structures. Typically, IL-6 exists as a monomer with an isoelectric point of 5.0. The gene encoding human IL-6 is located on chromosome 7p15-21 and consists of 4 introns and 5 exons. IL-6 possesses three receptor binding sites, including one specific binding site for the IL-6 receptor (IL-6R) protein and two binding sites for gp130, a signal-transducing protein.

Fig.1 IL-6 signal transduction.
Fig.1 IL-6 signal transduction. [2]

IL-6: The Central Player in Inflammatory Response and Immune Regulation

IL-6, the quintessential and pivotal member of the IL-6 family, is synthesized by various cell types, including T cells, B cells, macrophages, fibroblasts, among others. This cytokine assumes a significant role in crucial processes such as the inflammatory response, immune response, acute phase response, and tissue repair. IL-6 possesses the ability to stimulate immune cells to generate other inflammatory mediators, such as C-reactive protein (CRP) and interleukin-1 (IL-1), thereby promoting the inflammatory cascade. Moreover, IL-6 facilitates the proliferation and differentiation of B cells, exerting an influence on antibody production. Furthermore, it actively participates in multiple physiological and pathological processes, including tumor development, hematopoietic regulation, and neuroprotection.

IL-11: Hematopoietic Regulation and Anti-Inflammatory Effects

IL-11, another noteworthy member of the IL-6 family, is primarily synthesized by fibroblasts and bone marrow stromal cells. It assumes a critical role in the hematopoietic system, facilitating platelet growth and megakaryocyte differentiation. Additionally, IL-11 exhibits anti-inflammatory effects by inhibiting the production of inflammatory mediators and mitigating the development of inflammatory reactions.

Clinical significance

Clinically, IL-6 exhibits significant associations with the development of various diseases. Dysregulation of IL-6 expression can contribute to disease onset or exacerbation, with increased IL-6 levels being a common clinical manifestation.

Elevated IL-6 levels also correlate with disease progression, making the detection of IL-6 levels in patient body fluids valuable for assessing the patient's condition and treatment efficacy.

a) IL-6 and autoimmune diseases: Patients with rheumatoid arthritis, AIDS, Castleman's disease, and other conditions show elevated IL-6 levels.
b) IL-6 and inflammation/infection: Individuals with burns, postoperative complications, infections, and organ transplant recipients exhibit significantly increased serum IL-6 levels. IL-6 levels are also markedly elevated in COVID-19 patients.
c) IL-6 and tumors: Patients with tumors such as plasmacytoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia demonstrate significantly increased IL-6 levels, which correspond to disease severity.

Fig.2 Pleiotropic effect of interleukin 6(IL-6)
Fig.2 Pleiotropic effect of interleukin 6(IL-6) [3]

Research Areas

The research fields pertaining to the IL-6 family encompass several important aspects, including:

  1. Immune Regulation: IL-6 family molecules play a crucial role in immune regulation by influencing the development, activation, and function of immune cells, as well as participating in processes such as inflammation, immune response, and immune tolerance. Researchers strive to explore the mechanisms underlying the immune regulatory functions of the IL-6 family and its potential applications in treating immune-related diseases.
  2. Inflammation and Immune Diseases: IL-6 family molecules are closely associated with the occurrence and progression of inflammatory and immune-related diseases. For instance, IL-6 plays a pivotal role in conditions like rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Researchers aim to gain a deeper understanding of the precise mechanisms by which the IL-6 family operates in these diseases and develop therapeutics targeting IL-6 family molecules.
  3. Cell Proliferation and Differentiation: The impact of IL-6 family molecules extends to cell proliferation and differentiation processes. They can either promote or inhibit cell proliferation and differentiation, thereby affecting tissue development, regeneration, and tumor formation. Researchers are focused on studying the mechanisms underlying the actions of IL-6 family molecules in cell proliferation and differentiation, with the goal of uncovering their potential application in treating related diseases.
  4. Cancer: IL-6 family molecules play a critical role in the onset and progression of various cancers. They can promote tumor cell proliferation, invasion, metastasis, and influence the formation of the tumor microenvironment. Researchers are dedicated to studying the specific mechanisms by which the IL-6 family operates in cancer and developing anti-cancer therapeutic strategies that target IL-6 family molecules.

[1]. Sujin Kang et al. Historical overview of the interleukin-6 family cytokine.2020. J. Exp. Med. 2020 Vol. 217 No. 5
[2]. S. Kaur et al. A Panoramic Review of IL-6: Structure, Pathophysiological Roles and Inhibitors.2020. Bioorganic & Medicinal Chemistry.
[3]. Toshio Tanaka et al. Interleukin (IL-6) Immunotherapy.2018. Cold Spring Harb Perspect Biol
[4]. Toshio Hirano. IL-6 in inflammation, autoimmunity and cancer.2020. International Immunology, Vol. 33, No. 3, pp. 127–148

Interleukin Families

IL-1 Family

The IL-1 family, comprising IL-1α, IL-1β, IL-18, and related molecules, plays a crucial role in immune regulation and inflammation by activating immune cells, inducing intracellular signaling, and modulating biological effects through receptor binding.

IL-1 Family Details
IL-6 Family

The IL-6 family, comprising cytokines like IL-6, IL-11, IL-27, IL-31, LIF, and CNTF, plays vital roles in immune regulation, inflammatory response, as well as cell proliferation and differentiation within physiological processes.

IL-6 Family Details
IL-10 Family

The IL-10 family, consisting of IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and other members, plays a critical role in immune regulation, inflammatory response, and tissue repair.

IL-10 Family Details
IL-12 Family

The IL-12 family, comprising IL-12, IL-23, IL-27, and IL-35, possesses distinct structural, functional, and immunological attributes, playing a vital role in immunological research.

IL-12 Family Details
IL-17 Family

The IL-17 family contribute significantly to immune regulation and inflammatory responses, activating immune cells, inducing inflammatory mediator production, and participating in immune cell proliferation and tissue repair processes.

IL-17 Family Details
Other Interleukins

IL-2, IL-4, IL-5, IL-13, IL-14, IL-32, and IL-34 exhibit diverse functions and contribute to various aspects of immune regulation, inflammation, cell differentiation, and disease pathogenesis. Understanding their roles enhances our knowledge of immune responses and aids in the development of potential therapeutic strategies.

Other Interleukins Details