IL-6 Signaling Pathways
alpha
alpha
alpha
alpha
Cell Proliferation
(Inactive)
(Unknown)
Overview of the IL-6 Cytokine Family
IL-6 is the founding member of the IL-6 cytokine family, which also includes IL-11, IL-27 p28/IL-30, IL-31, Leukemia inhibitory factor (LIF), Oncostatin M (OSM), Cardiotrophin-like cytokine (CLC), Ciliary neurotrophic factor (CNTF), Cardiotrophin-1 (CT-1), and Neuropoietin. Like other IL-6 family cytokines, IL-6 contains four long alpha-helical chains that are arranged in an up-up-down-down topology. IL-6 is produced by numerous different cell types and plays a critical role in regulating the acute phase response, inflammation, hematopoiesis, liver regeneration, metabolic control, bone metabolism, and cancer progression. Classic IL-6 signaling is initiated by IL-6 binding to the membrane-bound form of the IL-6-specific receptor alpha subunit (IL-6 R alpha), which triggers its association with the signal-transducing gp130 receptor subunit. Association of gp130 with the IL-6-IL-6 R alpha complex promotes gp130 dimerization and formation of a heterohexameric complex consisting of IL-6, IL-6 R alpha, and gp130 in a 2:2:2 ratio. As classic IL-6 signaling relies on the expression of membrane-bound IL-6 R alpha, it is primarily limited to hepatocytes, macrophages, neutrophils, and resting lymphocytes. However, IL-6 can also activate trans-signaling in cells that express gp130, but lack expression of IL-6 R alpha. This requires binding of IL-6 to a soluble form of IL-6 R alpha, which can be generated by either alternative splicing or proteolytic cleavage. The IL-6/soluble IL-6 R alpha complex can then trans-activate IL-6 signaling pathways in gp130-expressing cells. As gp130 is ubiquitously expressed, trans-signaling allows a wider range of cells to respond to IL-6. Formation of either the IL-6 classic or trans-signaling ligand-receptor complexes leads to the activation of multiple intracellular signaling pathways including the Jak-STAT pathway, the Ras-MAPK pathway, the p38 and JNK MAPK pathways, the PI 3-K-Akt pathway, and the MEK-ERK5 pathway. Although both the classic and trans-signaling receptor complexes activate similar intracellular signaling pathways, several studies have suggested that classic signaling is required for the anti-inflammatory and regenerative effects of IL-6, while IL-6 trans-signaling promotes pro-inflammatory responses.
To learn more, please visit our IL-6 Family Research Area page.
IL-6
| Primary IL-6-Expressing Cells | Primary Biological Effects of IL-6 |
| Chondrocytes | Induces hepatocyte secretion of acute phase proteins |
| Endothelial cells | Promotes Th17 cell development and activity in the presence of TGF-beta; Suppresses the generation of inducible regulatory T cells |
| Epithelial cells | Enhances the proliferation of hematopoietic stem cells in the presence of IL-3 |
| Fibroblasts | Induces the maturation of megakaryocytes |
| Monocytes/macrophages | Stimulates the proliferation and differentiation of multiple lineages of hematopoietic progenitor cells; Considered to be a permissive factor of primitive hematopoiesis |
| Myocytes | Contributes to host defense against viral, bacterial, and fungal infections |
| Osteoblasts | Regulates inflammation: has both pro- and anti-inflammatory effects |
| Smooth muscle cells | Has chemokine-inducing activity that regulates the recruitment of T cells to sites of inflammation; Prevents T cell apoptosis |
| Synoviocytes | Induces the differentiation of CD8+ T cells into cytotoxic T cells |
| T cells | Induces the differentiation of T follicular helper cells |
| Induces the differentiation of B cells into antibody-secreting plasma cells | |
| Modulates osteoclast development and bone resorption | |
| Regulates metabolism; Has beneficial effects in the liver, skeletal muscle, white and brown adipose tissue, pancreas, and central nervous system | |
| Regulates liver regeneration | |
| Contributes to autoimmune and chronic inflammtory conditions including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, and inflammation-associated carcinogenesis |
| IL-6 Family Receptors - Products by Molecule | |||||
| Cytokine-like Factor 1 (CLF-1) | CNTF R alpha | gp130 | IL-6 R alpha | IL-11 R alpha | IL-27 R alpha |
| IL-31RA | LIF R alpha | OSM R beta | Sortilin | ||
