IL-6 Signaling Pathways

Click on the other IL-6 family cytokines listed below to see the signaling pathways that are activated by each cytokine. Refer to the table below each pathway to see a select list of cytokine-expressing cells or tissues and the primary biological effects induced by the different members of the IL-6 cytokine family.

IL-6
IL-6
sIL-6 R alpha
sIL-6 R alpha
IL-6
IL-6
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gp130
gp130
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sIL-6 R
alpha
sIL-6 R
alpha
IL-6
IL-6
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gp130
gp130
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IL-6
IL-6
sIL-6 R
alpha
sIL-6 R
alpha
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gp130
gp130
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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Trans Signaling
Trans Signaling
IL-6 Signaling
IL-6 Signaling
IL-6
IL-6
sIL-6 R alpha
sIL-6 R alpha
IL-6
IL-6
IL-6 R alpha
IL-6 R alpha
IL-6
IL-6
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gp130
gp130
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IL-6 R
alpha
IL-6 R
alpha
IL-6
IL-6
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gp130
gp130
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IL-6
IL-6
IL-6 R
alpha
IL-6 R
alpha
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gp130
gp130
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IL-6
IL-6
IL-6 R alpha
IL-6 R alpha
Classic Signaling
Classic Signaling
IL-6 R Complex
IL-6 R Complex
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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Tyk2
Tyk2
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Jak2
Jak2
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Jak1
Jak1
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IRS1/2
IRS1/2
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SHP-2
SHP-2
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Grb2
Grb2
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SOS
SOS
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Gab1/2
Gab1/2
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MEK5
MEK5
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ERK5
ERK5
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PI 3-K
PI 3-K
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PIP2
PIP2
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PIP3
PIP3
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PDK-1
PDK-1
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Akt/PKB
Akt/PKB
Cell Survival
Cell Proliferation
Cell Survival
Cell Proliferation
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TSC1/2
(Inactive)
TSC1/2
(Inactive)
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Rheb
Rheb
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GTP
GTP
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mTORC1
mTORC1
p70 S6K
p70 S6K
RPS6
RPS6
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4EBP1
4EBP1
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eIF4E
eIF4E
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eIF4E
eIF4E
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4EBP1
4EBP1
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Protein Synthesis
Protein Synthesis
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STAT1
STAT1
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STAT3
STAT3
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STAT5
STAT5
STAT Dimer
STAT Dimer
STAT Dimer
STAT Dimer
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SHP-2 or SHC
SHP-2 or SHC
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Grb2
Grb2
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SOS
SOS
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Gab1/2
Gab1/2
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Vav
Vav
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Rac1
Rac1
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MAPKKK
(Unknown)
MAPKKK
(Unknown)
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MKK4
MKK4
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p38
p38
JNK
JNK
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PKC delta
PKC delta
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AP-1
AP-1
Cell Proliferation
Cell Proliferation
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Ras
Ras
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Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
p90 RSK
p90 RSK
Transcription Factor
Transcription Factor

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