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IL-6 Signaling Pathway

Figure 1. IL-6 Signaling Pathway.

An overview of IL-6

Adipose tissue has long been thought to be just a “warehouse” for storing lipids since it has been found that fat cells secrete certain cytokines and hormones which play an important role in adipose tissue itself and other organ tissues. It is recognized that adipose tissue is not only a place to store fat, but also an important endocrine tissue. Adipose tissue plays an important role in maintaining energy and cardiovascular homeostasis, glucose and lipid metabolism, immune response, and is closely linked to obesity, diabetes, and their complications. White adipose tissue (WAT) is now widely thought to secrete many peptide hormones and cytokines such as leptin, tumor necrosis factor (TNF-α), plasminogen activator inhibitor-1 (PAI-1), acylation stimulation Protein (ASP), angiotensinogen, adipsin, adiponectin and resistin. The vasoactive hormones and factors secreted by fat cells are collectively referred to as adipocytokine. Interleukin 1, interleukin 6, interleukin 8 and interleukin 10 are important adipocytokines. IL-6 is a strong inducer of C-reactive protein synthesis in the liver. Increased levels of IL-6 in plasma can increase the level of C-reactive protein, which can cause blood clotting on the surface of the vascular endothelium. IL-6 binds to its soluble receptor to induce endothelial expression of monocyte chemotactic proteins and various adhesion molecules, stimulate leukocyte agglutination and damage endothelial cells. In addition, elevated IL-6 levels also promote the release of TNF-α from macrophages, aggravating damage to vascular endothelial cells. IL-6 is also involved in the metabolism of fat and glucose, which promotes lipolysis and free fatty acid release, increases liver triglycerides, and causes insulin resistance. Recombinant IL-6 is used in both rodents and humans to cause hyperglycemia and high insulin blood. However, there is no report on the improvement of glucose and lipid metabolism by inhibiting IL-6. Because the immune regulatory function of IL-6 is very important, correcting abnormal glucose and lipid metabolism by inhibiting IL-6 may cause other adverse reactions in patients, and it is not worth the candle.

IL-6 family

The IL-6 family consists primarily of IL-6 and IL-6 receptors. IL-6 is a glycoprotein consisting of 212 amino acids with a molecular weight of 26 kD. It is a cytokine with extensive immunomodulatory effects. Recent studies have found that normal human adipocytes can secrete IL-6. The amount of IL-6 secreted by adipose tissue in obese patients increased significantly, reaching 25% of total plasma IL-6 content. Human IL-6R is a glycoprotein formed by glycosylation of a 50 KD precursor molecule. Its alpha-strand cDNA encodes a protein of 468 amino acids, including a signal peptide consisting of 19 amino acids, and 339 extracellular regions. The nitrogen acid has a transmembrane region of 28 amino acids and a functional region within the cytoplasm of 82 amino acids. The extracellular domain consists of an Ig-like region (approximately 100 amino acids), two oral fibronectin structures (each containing 100 amino acids), and a homologous region of one cytokine receptor containing four conservative Cys and one WSXWS. The Ig-like region is not very important in the recognition of the ligand and the generation of the signal, but the internalization of the receptor and the stability of the protein may play a role. The molecular weight of gp130 is 130 kDa, and there are 14 potential N-glycosylation sites. The extra membranous region, a transmembrane region, and cytoplasmic region are composed of 597, 22 and 227 amino acids, respectively. There is an Ig C2 region in the extracellular region and the structure of six oral fibronectin proteins. There are four conserved Cys and WSXWS structures between the second and third structural regions. Gp130 cannot directly bind to ligand IL-6. Under physiological conditions, IL-6 binds to IL-6R to change the conformation of IL-6R and rapidly binds to two gp130 molecules to form a high-affinity binding site, then passes the signal through the gp130 subunit.

IL-6 signaling pathway

  1. IL-6 signaling pathway cascade
    IL-6R protein can exist in both membrane-bound and soluble (aIL-6R) forms, although cells that do not express IL-6R do not respond to IL-6 alone, they can be stimulated by a complex formed by IL-6 and aIL-6R. Releasing the IL-6R protein presenting cells, which presents a gp130-responsive response to IL-6 cytokines, is a method recently called "signaling". In addition, IL-6 responsive cells are very sensitive to IL -6R. Those cells that express gp130 but do not respond to IL-6 include hematopoietic progenitors, osteoclasts, and neuronal cells. IL-6 forms a complex with a specific IL-6R and can bind with two gp130 with high affinity to form a tetramer or hexamer IL-6/IL-6R/gp130 complex, causing a series of signals. Gp130 conducts biological signaling through two pathways: the JAK/STAT pathway and the Ras/MAPK (mitogen-activated protein kinase) pathway. The JAK/STAT pathway is a member of a family of tyrosine protein-activated kinases. STAT (signaling and transcriptional activator) proteins are their substrates. JAK kinases (JAK I, JAK2, and TYK2) bind to gp130 or ILFR (leukemia inhibitory factor receptor) prior to activation. Among these JAK kinases, the role of JAKI in IL-6 signaling is particularly important. Gp130: ILFR dimers induce phosphorylation, activation of these kinases, and phosphorylation of six tyrosine residues on gp130 and ILFR. These phosphorylated tyrosine residues can recruit a variety of molecules with SH-2 structural domain such as SHP-2, Shc, STAT3, and STAT1. STAT3 and STAT1 are transcription factors, which can be passed after tyrosine phosphorylation. SH-2 interacts with phosphorylated tyrosine to form a homologous or heterodimer. The dimer is separated from its binding site (such as JAKI) and transferred to the nucleus after tyrosine phosphorylation, thereby activating specific DNA binding sequences so as to promote gene expression. Ras/MAPK pathway: gp130 activation induces the formation and activation of the complex of Shc and Grb2 (growth factor receptor binding protein 2) and binds to Sos (guanine core release protein). Activation of the Ras protein (membrane-bound guanosine triphosphatase) requires the interaction of these proteins. Ras activation usually induces activation of downstream signaling proteins such as MAPK cascade phosphorylation, and MAPK kinases are involved in regulating cell growth. The substrates for phosphorylation of MAPK are c-Myc, c-Jun, c-Fos and the like.
  2. Pathway regulation
    The regulation of the IL-6 signaling pathway is very precise, and several important signal conditioning methods are listed here. Studies have shown that palmitic acid has a certain effect on the regulation of the IL-6 signaling pathway. Palmitic acid promotes the secretion of IL-6 in omental adipocytes in non-diabetic patients, and it is concentration-dependent, RSG can reverse this promotion, and the reversal effect, strong or weak, is related to the concentration of RSG. The reversal effect of high concentration of RSG is stronger. Palmitate promotes the secretion of IL-6 in omental adipocytes in diabetic patients, and RSG can reverse this promotion. The size of the high-concentration palmitic acid promotion and the strength of the reversal of rosiglitazone were not significantly different between diabetic and non-diabetic individuals. LPS: Endotoxin is also present in the peripheral blood of healthy people (eg, lipopolysaccharide, LPS). The activity of LPS may be related to a high-fat diet and dyslipidemia. In humans, the input of triglycerides can cause the same reaction as LPS and promote inflammation. The TLR4 signaling pathway is a more important inflammatory pathway, and both LPS and free fatty acids can act as ligands for TLR4 to activate TLR4. Studies have confirmed that the expression of TLRs in adipose tissue of obese patients is increased. In recent years, studies have found that TLRs are closely related to obesity as a risk factor for atherosclerosis. Studies have shown that LPS can up-regulate the expression of TLR4 mRNA in 3T3 - L1 adipocytes and activate STAT5 signaling pathway, suggesting that LPS may be involved in the induction of an inflammatory state of adipocytes. The study found that LPS promoted the increase in IL-6 production in adipocytes, consistent with the findings of Shi and Flier et al. However, the specific mechanism remains to be further studied.
  3. Relationship with disease
    Diabetes
    In vivo studies in patients with type 2 diabetes found that the concentration of IL-6 in diabetic patients was significantly higher than that in normal subjects. The severity of diabetes is positively correlated with the concentration of IL-6. The intervention of IL-6 release and reduction of IL-6 concentration have a certain effect on the treatment of diabetes, but the specific mechanism remains to be further studied.
    Myeloma
    IL-6 is closely related to myeloma and can promote the proliferation of most bone tumor cells. The activity of IL-6R in multiple bone tumors is at its physiological level, which can increase the sensitivity of myeloma cells to IL-6. Many studies have shown that the level of IL-6R is significantly elevated in the serum of patients with multiple pelvic pain, and IL-6R is associated with the degree of development of multiple bone tumors in the circulation. Therefore, circulating levels of IL-6R are also expected to be valuable prognostic indicators.

References

  1. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harbor Perspectives in Biology. 2014, 6(10):016295.
  2. Wang S W, Sun Y M. The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer (Review). International Journal of Oncology. 2014, 44(4):1032-1040.
  3. Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Seminars in Immunology. 2014, 26(1):54-74.
  4. Babon J J, Varghese L N, Nicola N A. Inhibition of IL-6 family cytokines by SOCS3. Seminars in Immunology. 2014, 26(1):13-19.
  5. Stefan R J. IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6. International Journal of Biological Sciences. 2012, 8(9):1237.

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