IL-6 Family Ligand Review

The IL-6 family of cytokines is a group of functionally and structurally related proteins. These cytokines regulate a variety of complex biological processes, including hematopoiesis, immune response, inflammation, proliferation, differentiation, mammalian reproduction, cardiovascular action, and neuronal survival.

Activation of all cytokines in the IL-6 family involves signaling via the Janus Kinase/Signal Transducer and Activator of Transcription(JAK/STAT) pathway.

These cytokines are referred to as IL-6 family because all members of this family utilize glycoprotein 130 as a common signal transducer within their receptor complex that is required for signaling.

The following will briefly introduce each IL-6 family ligand, including Interleukin-6 (IL-6), Interleukin-11 (IL-11), Interleukin-31 (IL-31), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), leptin (OB), cardiotrophin-1 (CT-1), novel neurotrophin-1/B cell stimulating factor-3 or cardiotrophinlike cytokine (CLC), and neuropoietin (NP).

Interleukin-6

Interleukin-6 (IL-6) is a member of the IL-6 family ligands. IL-6, the family namesake, is by far the most extensively characterized cytokine of this family, despite the shared use of a common receptor subunit, GP130, among the cytokines of this family.

IL-6 is a pleiotropic cytokine that regulates various physiological processes in multiple tissues, including inflammation, hematopoiesis, immune responses, and host defense mechanisms.

Interleukin-11

IL-11 is a member of the IL-6 family of ligands, which includes IL-6, LIF, OSM, CNTF, CT-1, CLC, IL-27 and IL-31.

While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs.

Interleukin-31

Interleukin-31, produced mainly by activated CD4+ T cells, is a newly discovered member of the gp130/IL-6 family ligands.

Unlike all the other family members, IL-31 does not engage gp130. Its receptor heterodimer consists of a unique gp130-like receptor chain IL-31RA, and the receptor subunit OSMRβ that is shared with another family member oncostatin M (OSM).

Binding of IL-31 to its receptor activates JAK/STAT, PI3K/AKT and MAPK pathways. IL-31 acts on a broad range of immune- and non-immune cells and therefore possesses potential pleiotropic physiological functions, including regulating hematopoiesis and immune response, causing inflammatory bowel disease, airway hypersensitivity and dermatitis.

Oncostatin M

Oncostatin M (OSM) shares two primary similarities with LIF. First, human oncostatin was identified for its ability to inhibit the growth of cancer lines. Second, OSM shares substantial sequence identity with LIF.

Like other IL-6 family ligands, OSM can modulate a variety of biological processes and has some functional overlap with LIF. It has been suggested that OSM and LIF evolved by gene duplication relatively recently.

Unlike CT-1 and some other IL-6 family ligands, OSM has its own specific receptor that heterodimerizes with gp130. The oncostatin receptor, OSMRβ, appears to mediate the majority of the effects of OSM.

Ciliary Neurotrophic Factor

Ciliary neurotrophic factor (CNTF) is a 22-kDa protein predicted to share with leukemia inhibitory factor (LIF) and interleukin-6 a common amphipathic helical domain. Consistent with this prediction, the CNTF receptor complex is composed of the CNTF alpha receptor, the LIF beta receptor and gp130 a signalling molecule for LIF and interleukin-6.

Ciliary neurotrophic factor (CNTF) is expressed by glial cells in peripheral nerves and in the central nervous system that was originally identified for its role in the differentiation and survival of neuronal cell types.

Leukemia Inhibitory Factor

Leukemia inhibitory factor (LIF) is one of the most studied IL-6 family ligands and was originally indentified for its ability to inhibit the growth of a leukemic cell line. The most widely recognized function of LIF is its ability to maintain the totipotency of embryonic
stem cells.

However, LIF exerts a wide variety of pleitropic actions, including acting as a stimulus for platelet formation, modulating proliferation of a variety of cell types, enhancing survival of peripheral neurons, promoting bone formation, and enhancing acute phase production by hepatocytes.

Cardiotrophin-1

Cardiotrophin-1 (CT-1) is a IL-6 family ligand member that was identified in 1995 in a cDNA library derived from mouse embryoid bodies and was shown to support in vitro cardiomyocyte survival and hypertrophy.

CT-1 is a 200 amino acid protein with a molecular mass of approximately 21.5 kD. CT-1 mRNA expression has been detected at high levels in the heart, skeletal muscle, and liver, as well as in fetal heart, lung, and kidney. Lower amounts have also been detected in a variety of other tissues.

Both functional and receptor binding studies in cultured cardiomyocytes have shown that CT-1 signals through the gp130/LIFR heterodimer without the further requirement for an -subunit.

The majority of studies on CT-1 indicate a role of this IL-6 family ligand member in a variety of heart pathologies, including hypertension, myocardial infarction, ischemia, and cardiomyopathy.

Neuropoeitin

Neuropoeitin (also known as cardiotrophin-2, NP/CT-2) is a member of the IL-6 family of cytokines. Neuropoeitin was characterized as a potential regulator of murine central nervous system development, with the ability to modulate motor neuron survival in vitro. Neuropoeitin was shown to be highly expressed in mouse embryonic neuroepithelia and can induce neuroepithelial cells to differentiate into astrocytes.

Cardiotrophin-Like Cytokine

Cardiotrophin-like cytokine (CLC, also known as Novel Neurotrophin-1/NNT-1 or B cell-stimulating factor-3/BSF-3) was identified as a neurotrophic factor that has B cell stimulating effects, promotes survival of neuronal cells, and modulates corticotroph cell function.

Cardiotrophin-like cytokine belongs to the interleukin-6/IL-6 family. Though highly expressed in the spleen and lymph nodes, CLC is also expressed in a variety of other tissues, which suggests important biological roles in cellular functions.

Leptin

Leptin, the ob (obese) gene product, has a structure similar to that of the IL-6 family of cytokines. Furthermore, its receptor (OBR) is homologous to gp130. Both Janus kinases and signal transducers and activators of transcription are involved as downstream components of leptin and IL-6 signaling, which demonstrates several similarities between leptin and the IL-6 family.

Granulocyte Colony-Stimulating Factor

The granulocyte colony-stimulating factor (G-CSF/CSF3) regulates haematopoietic cell proliferation and differentiation, and G-CSF almost exclusively stimulates the colony formation of granulocytes from committed precursor cells in semi-solid agar culture.

G-CSF belongs to IL-6 family ligands, because G-CSF receptor shares the glycoprotein 130 with IL-6 receptor family. Glycoprotein 130 is important for signal transduction following cytokine engagement.

References

1. A White, U., & M Stephens, J. (2011). The gp130 receptor cytokine family: regulators of adipocyte development and function. Current pharmaceutical design, 17(4), 340-346.
2. Richardson, P. M. (1994). Ciliary neurotrophic factor: a review. Pharmacology & therapeutics, 63(2), 187-198.
3. Putoczki, T. L., & Ernst, M. (2015). IL-11 signaling as a therapeutic target for cancer.
4. Zhang, Q., Putheti, P., Zhou, Q., Liu, Q., & Gao, W. (2008). Structures and biological functions of IL-31 and IL-31 receptors. Cytokine & growth factor reviews, 19(5), 347-356.