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IL-6 Family

Overview

The Interleukin-6 family (IL-6 family) is a group of cytokines consisting of IL-6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT-1). They are grouped into one family because the receptor complex of each cytokine contains two (IL-6 and IL-11) or one molecule (all others cytokines) of the signaling receptor subunit gp130. IL-6 family cytokines have overlapping but also distinct biologic activities and are involved among others in the regulation of the hepatic acute phase reaction, in B-cell stimulation, in the regulation of the balance between regulatory and effector T cells, in metabolic regulation, and in many neural functions. Blockade of IL-6 family cytokines has been shown to be beneficial in autoimmune diseases, but bacterial infections and metabolic side effects have been observed. Recent advances in cytokine blockade might help to minimize such side effects during therapeutic blockade.

Members of IL-6 Family

Table 1. IL-6 family related products

IL-6 Family Ligands

Cardiotrophin-1 (CT-1) CLC CNTF
IL-6 IL-11 IL31
Leptin LIF OSM
IL-6 Family Receptors CNTFR CRLF1 IL6ST
IL6R IL6RA IL11RA
IL31RA LIFR OSMR

  • IL-6

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory cytokine. In humans, it is encoded by the IL-6 gene. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. IL-6 also plays a role in fighting infection, as IL-6 has been shown in mice to be required for resistance against bacterium Streptococcus pneumoniae. IL-6 is an important mediator of fever and of the acute phase response. It is capable of crossing the blood-brain barrier and initiating synthesis of PGE2 in the hypothalamus, thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs).

IL-6 Family

Figure 1. IL-6 protein

  • IL-11

Interleukin 11 (IL-11) is a protein that in humans is encoded by the IL-11 gene. IL-11 is a multifunctional cytokine first isolated in 1990 from bone marrow-derived stromal cells. It is a key regulator of multiple events in hematopoiesis, most notably the stimulation of megakaryocyte maturation. It is also known under the names adipogenesis inhibitory factor (AGIF) and oprelvekin. The human IL-11 gene, consisting of 5 exons and 4 introns, is located on chromosome 19, and encodes a 23 kDa protein. IL-11 is a member of the IL-6-type cytokine family, distinguished based on their use of the common co-receptor gp130. Signal specificity is provided by the IL-11Rα subunit. Signal transduction is initiated upon binding of IL-11 to IL-11Ralpha and gp130, facilitating the homodimerization of gp130 molecules. This permits gp130-associated Janus kinases (JAK) to become activated and phosphorylate intracellular tyrosine residues on gp130.

  • CNTF

Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene. The protein encoded by this gene is a polypeptide hormone and neurotrophic factor whose actions have mainly been studied in the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neural populations including astrocytes. It is a hypothalamic neuropeptide that is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks.

IL-6 Family

Figure 2. CNTF protein

  • LIF

Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. LIF is normally expressed in the trophectoderm of the developing embryo, with its receptor LIFR expressed throughout the inner cell mass. Embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass as well as their source of LIF. Recombinant LIF has been produced in plants by InVitria.

  • OSM

Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene. OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory factor (LIF) in both structure and function. OSM signals through cell surface receptors contain the protein gp130. The type I receptor is composed of gp130 and LIFR, the type II receptor is composed of gp130 and OSMR.

IL-6 Family

Figure 3. OSM protein

  • CT-1

Cardiotrophin-1 (CT-1) is a cytokine. It is a cardiac hypertrophic factor of 21.5 kDa and a protein member of the IL-6 cytokine family. CT-1 is highly expressed in the heart, skeletal muscle, prostate and ovary, and lower levels in lung, kidney, pancreas, thymus, testis and small intestine.

Cellular functions

IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10.

As a signaling molecule, interleukin 11 has a variety of functions associated with its receptor interleukin 11 receptor alpha; such functions include placentation and to some extent of decidualization. IL11 has been expressed to have a role during implantation of the blastocyst in the endometrium of the uterus; as the blastocyst is imbedded within the endometrium, the extravillous trophoblasts will invade the maternal spiral arteries for stability and the transfer of essential life-sustaining elements via the maternal and fetal circulatory systems.

CNTF may stimulate nerve cells to survive. It has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone-forming cells (osteoblasts).

LIF is often added to stem cell culture media as an alternative to feeder cell culture, due to the limitation that feeder cells present by only producing LIF on their cell surfaces. Feeder cells lacking the lif gene do not effectively support stem cells. LIF is typically added to stem cell culture medium to reduce spontaneous differentiation.

OSM is synthesized by stimulated T-cells and monocytes. The effects of OSM on endothelial cells suggest a pro-inflammatory role for OSM. Endothelial cells possess a large number of OSM receptors. Stimulation of a primary endothelial culture (HUVEC) with hOSM results in delayed but prolonged upregulation of P-selectin, which facilitates leukocyte adhesion and rolling, necessary for their extravasation. OSM also promotes the production of IL-6 from these cells.

CT-1 exerts its cellular effects by interacting with the glycoprotein 130 (gp130)/leukemia inhibitory factor receptor beta (LIFR) heterodimer. In addition, CT-1 activates phosphatidylinositol 3-kinase (PI-3 kinase) in cardiac myocytes and enhances transcription factor NF-κB DNA -binding activities.

Role in disease

IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as diabetes, atherosclerosis, depression, alzheimer's disease, systemic lupus erythematosus, multiple myeloma, prostate cancer, behçet's disease, and rheumatoid arthritis. Hence, there is an interest in developing anti-IL-6 agents as therapy against many of these diseases. The first is tocilizumab, which has been approved for rheumatoid arthritis, castleman's disease and systemic juvenile idiopathic arthritis. Others are in clinical trials.

IL-11 has been demonstrated to improve platelet recovery after chemotherapy-induced thrombocytopenia, and induce acute phase proteins, modulate antigen-antibody responses, as well as participating in the regulation of bone cell proliferation, and differentiation of IL-11 causes bone-resorption. It stimulates the growth of certain lymphocytes and, in the murine model, stimulates an increase in the cortical thickness and strength of long bones. In addition to having lymphopoietic/hematopoietic and osteotrophic properties, it has functions in many other tissues, including the brain, gut, testis and bone.

In a human study examining the usefulness of CNTF for treatment of motor neuron disease, CNTF produced an unexpected and substantial weight loss in the study subjects.

LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells, thus preventing their continued growth. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on bone metabolism, cachexia, neural development, embryogenesis and inflammation.

OSM is proving to be important in liver development, haematopoeisis, inflammation and possibly CNS development. It is also associated with bone formation and destruction.

CT-1 is associated with the pathophysiology of heart diseases, including hypertension, myocardial infarction, valvular heart disease, and congestive heart failure.

References:

1. Grenier A, Dehoux M, Boutten A. "Oncostatin M production and regulation by human polymorphonuclear neutrophils". Blood. 1999, 93 (4): 1413–21.
2. Aghajanova L. "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences. 2004, 1034: 176–83.
3. Chen HF, Lin CY, Chao KH. "Defective production of interleukin-11 by decidua and chorionic villi in human anembryonic pregnancy". J. Clin. Endocrinol. Metab. 2002, 87 (5): 2320–8.
4. Banks WA, Kastin AJ, Gutierrez EG. "Penetration of interleukin-6 across the murine blood-brain barrier". Neuroscience Letters. 1994,179 (1–2): 53–6.
5. McGregor NE, Poulton IJ, Walker EC. "Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling". Calcified Tissue International. 2010, 86 (3): 261–70.

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