IL-12 Family Signaling Pathways

Click on one of the IL-12 family cytokines below to see a list of select ligand-producing cells, major target cells, and the primary biological effects induced by each cytokine.

IL-12
IL-12
p35
p35
p40
p40
IL-12 R
beta 1
IL-12 R
beta 1
IL-12 R
beta 2
IL-12 R
beta 2
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Tyk2
Tyk2
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Jak2
Jak2
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STAT1
STAT1
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STAT3
STAT3
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STAT4
STAT4
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STAT5
STAT5
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STAT4 Dimer
STAT4 Dimer
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STAT4
STAT4
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IFN-gamma
IFN-gamma
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IL-23
IL-23
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p19
p19
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p40
p40
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IL-23 R
IL-23 R
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IL-12 R
beta 1
IL-12 R
beta 1
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Jak2
Jak2
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Tyk2
Tyk2
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STAT1
STAT1
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STAT3
STAT3
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STAT4
STAT4
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STAT5
STAT5
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STAT3 Dimer
STAT3 Dimer
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STAT4 Dimer
STAT4 Dimer
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STAT3
STAT3
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STAT4
STAT4
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IL-21
IL-21
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ROR gamma t
ROR gamma t
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IL-23 R
IL-23 R
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IL-17A
IL-17A
IL-27
IL-27
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p28
p28
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EBI3
EBI3
IL-27 R
alpha/
WSX-1
IL-27 R
alpha/
WSX-1
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gp130
gp130
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Jak1
Jak1
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Jak1
Jak1
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Jak2
Jak2
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Tyk2
Tyk2
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STAT1
STAT1
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STAT3
STAT3
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STAT4
STAT4
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STAT5
STAT5
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STAT1 Dimer
STAT1 Dimer
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STAT1-STAT3
Heterodimer
STAT1-STAT3
Heterodimer
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STAT3 Dimer
STAT3 Dimer
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STAT1
STAT1
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STAT3
STAT3
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T-bet
T-bet
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GATA-3
GATA-3
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IL-35
IL-35
p35
p35
EBI3
EBI3
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gp130
gp130
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IL-12 R
beta 2
IL-12 R
beta 2
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Jak1
Jak1
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Jak2
Jak2
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Tyk2
Tyk2
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Jak2
Jak2
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STAT3
STAT3
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STAT1
STAT1
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STAT4
STAT4
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STAT1-STAT4
Heterodimer
STAT1-STAT4
Heterodimer
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STAT1-STAT4
STAT1-STAT4
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IL-12 alpha/p35
IL-12 alpha/p35
EBI3
EBI3
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gp130
gp130
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gp130
gp130
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Jak1
Jak1
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Jak2
Jak2
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Tyk2
Tyk2
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Jak1
Jak1
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Jak2
Jak2
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Tyk2
Tyk2
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STAT1
STAT1
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STAT1 Dimer
STAT1 Dimer
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IL-12 R
beta 2
IL-12 R
beta 2
IL-12 R
beta 2
IL-12 R
beta 2
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Jak2
Jak2
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Jak2
Jak2
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STAT4
STAT4
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STAT4 Dimer
STAT4 Dimer
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IL-27 R
alpha/
WSX-1
IL-27 R
alpha/
WSX-1
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Jak1
Jak1
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Jak2
Jak2
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STAT1
STAT1
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STAT3
STAT3
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IL-39
IL-39
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p19
p19
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EBI3
EBI3
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IL-23 R
IL-23 R
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gp130
gp130
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Jak1
Jak1
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Jak2
Jak2
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Tyk2
Tyk2
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Jak2
Jak2
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STAT1
STAT1
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STAT1 Dimer
STAT1 Dimer
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STAT1
STAT1
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STAT3
STAT3
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STAT3 Dimer
STAT3 Dimer
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STAT3
STAT3
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p19
p19
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EBI3
EBI3
Primary Cytokine-Producing Cells
  • Dendritic cells
  • Macrophages
  • Monocytes
  • Neutrophils
  • B cells
Receptor-Expressing Cells
  • IL-12 R beta 1: Constitutively expressed on T cells, natural killer cells, B cells, dendritic cells, macrophages, and microglia
  • IL-12 R beta 2: Activated naïve T cells, natural killer cells, and dendritic cells
Primary Biological Effects
  • Pro-inflammatory
  • Promotes the differentiation of naïve CD4+ T cells into Th1 cells
  • Enhances the cytotoxicity of natural killer cells and cytotoxic T lymphocytes
  • Induces IFN-gamma production by T cells and natural killer cells
  • Stimulates proliferation of T cells and natural killer cells
  • Influences T cell trafficking
Primary Cytokine-Producing Cells
  • Dendritic cells
  • Macrophages
  • Monocytes
  • CD4+CD45RBlow Memory T cells
Receptor-Expressing Cells
  • IL-23 R: Memory T cells, Th17 cells, gamma delta T cells, natural killer cells, innate lymphoid cells, neutrophils
  • IL-12 R beta 1: Constitutively expressed on T cells, natural killer cells, B cells, dendritic cells, macrophages, and microglia
Primary Biological Effects
  • Pro-inflammatory
  • Promotes the expansion and maintenance of Th17 cells
  • Promotes memory T cell activation and proliferation
  • Stimulates IL-17-mediated neutrophil recruitment to sites of infection
  • Up-regulated in several inflammation-associated pathologies
Primary Cytokine-Producing Cells
  • Dendritic cells
  • Macrophages
  • Monocytes
Receptor-Expressing Cells
  • IL-27 R alpha/WSX-1: Naïve, effector, and memory CD4+ and CD8+ T cells, natural killer cells, natural killer T cells, dendritic cells, B cells, monocytes, macrophages, mast cells, and endothelial cells
  • gp130: Ubiquitously expressed by immune and non-immune cell types
Primary Biological Effects
  • Pro- and Anti-inflammatory
  • Promotes early Th1 commitment through induction of T-bet
  • Enhances naïve CD4+ T cell proliferation
  • Inhibits Th17 differentiation and IL-17 production
  • Induces the conversion of activated, differentiated effector T cells into IL-10-producing, immunosuppressive T regulatory type I-like (Tr1-like) cells
  • Promotes the effector functions of natural killer cells and CD8+ T cells
  • Facilitates the development and survival of follicular helper T (Tfh) cells via the induction of IL-21 and other hallmark Tfh genes
  • Modulates B cell Ig class switching
  • Induces mast cell activation
Primary Cytokine-Producing Cells
  • Regulatory T cells (Tregs)
  • Regulatory B cells (Bregs)
Receptor-Expressing Cells
  • IL-12 R beta 2: Activated naïve T cells, natural killer cells, and dendritic cells
  • gp130: Ubiquitously expressed by immune and non-immune cell types
  • IL-27 R alpha/WSX-1: Naïve, effector, and memory CD4+ and CD8+ T cells, natural killer cells, natural killer T cells, dendritic cells, B cells, monocytes, macrophages, mast cells, and endothelial cells
Primary Biological Effects
IL-12 R beta 2-gp130 Heterodimeric Receptor:
  • Anti-inflammatory
  • Suppresses the proliferation of conventional T cells
  • Induces the conversion of naïve conventional T cells into IL-35-producing induced regulatory T cells (iTr35 cells)
  • Enhances regulatory T cell proliferation
IL-12 R beta 2-IL-12 R beta 2 or gp130-gp130 Homodimeric Receptors:
  • Partial suppression of the proliferation of conventional T cells
IL-12 R beta 2-IL-27 R alpha/WSX-1 Heterodimeric Receptor:
  • Induces the conversion of B cells into IL-35-, IL-10-producing regulatory B cells and promotes their expansion
Primary Cytokine-Producing Cells
  • Activated B cells
  • Keratinocytes
Receptor-Expressing Cells
  • IL-23 R: Memory T cells, Th17 cells, gamma delta T cells, natural killer cells, innate lymphoid cells, neutrophils
  • gp130: Ubiquitously expressed by a variety of immune and non-immune cell types
Primary Biological Effects
  • Regulates inflammatory responses
  • Induces neutrophil expansion or differentiation
  • Stimulates BAFF secretion by neutrophils
  • Associated with the pathophysiology of SLE and other autoimmune diseases

Overview of the IL-12 Cytokine Family

The IL-12 family of heterodimeric cytokines includes IL-12, IL-23, IL-27, IL-35, and IL-39. The first three of these cytokines are produced primarily by dendritic cells, macrophages, and monocytes, while IL-35 is produced by regulatory T (Treg) and regulatory B (Breg) cells, and IL-39 is secreted by activated B cells and keratinocytes. Each of the IL-12 family cytokines consists of two subunits: an alpha chain (p19, p28, or p35) with a four alpha-helix bundle structure and a beta chain (p40 or EBI3) that is homologous to the soluble class I cytokine receptor chains. The alpha and beta chain subunits are shared among different members of the IL-12 family. IL-12 is composed of the p35 alpha chain and the p40 beta chain, which are covalently linked by a disulfide bond to form the IL-12 p70 protein. IL-23 also contains the IL-12 p40 subunit, but in this case, it is disulfide-linked to the p19 alpha chain, which shares homology with IL-12 p35. Similarly, IL-27, IL-35, and IL-39 consist in part of a shared IL-12/IL-23 p40-related protein known as Epstein-Barr virus-induced gene 3 (EBI3). EBI3 pairs with either p28, a polypeptide related to IL-12 p35, to form IL-27, or with p35 to form IL-35, or p19 to form IL-39.

Due to similarities in the subunit composition of the IL-12 family cytokines, many of the receptors for these cytokines also have common chains and activate seemingly comparable downstream signaling pathways. IL-12 and IL-23 both signal through heterodimeric receptor complexes that contain IL-12 R beta 1 paired with either IL-12 R beta 2 for the IL-12 receptor or with IL-23 R for the IL-23 receptor. Likewise, the receptor complexes for IL-27, IL-35, and IL-39 all contain gp130, a common receptor subunit shared with the IL-6 family cytokines. gp130 couples with IL-27 R alpha/WSX-1 to form the IL-27 receptor complex, with IL-12 R beta 2 to form the IL-35 receptor complex in T cells, or with IL-23 R to form the IL-39 receptor complex. Additionally, homodimers of gp130 or IL-12 R beta 2 have also been shown to elicit a partial IL-35-induced response in T cells, while in B cells, IL-35 has been shown to signal through a receptor complex comprised of IL-12 R beta 2 and IL-27 R alpha/WSX-1. Following receptor binding, all members of the IL-12 family trigger the activation of Jak2 along with Tyk2 and/or Jak1, leading to the phosphorylation of a subset of STAT proteins, which then homodimerize or heterodimerize and translocate to the nucleus where they induce the expression of target genes. Although multiple STAT proteins may be activated by each IL-12 family cytokine, typically the biological effects associated with different cytokines have been attributed to the activities of one or two STAT proteins. The primary STATs required for signaling by each IL-12 family cytokine are shown as the larger, more brightly colored STAT molecules in the signaling pathways presented in the graphic (refer to the key at the bottom of the pathway).

Despite similarities in the signaling pathways that they activate, cytokines belonging to the IL-12 family have distinct effects on the immune response. A number of these effects are brought about by the ability of the IL-12 family cytokines to differentially regulate the activities of specific T cell subsets. Signaling induced by IL-12 promotes the differentiation of naïve CD4+ T cells into Th1 cells, induces proliferation and IFN-gamma production by natural killer (NK) cells and T cells, and enhances the cytotoxicity of NK cells and cytotoxic T lymphocytes. In contrast, IL-23 signaling is involved in the stabilization and maintenance of Th17 cells, promotes memory T cell activation, and stimulates IL-17-mediated neutrophil recruitment to sites of infection. Although these activities demonstrate that IL-12 and IL-23 induce different immune responses, both can be characterized as pro-inflammatory.

IL-27 is unique in that it has both pro-inflammatory and anti-inflammatory effects. IL-27 drives inflammation by promoting the early commitment of naïve CD4+ T cells to a Th1-specific lineage through the induction of T-bet, but it also suppresses inflammation by inhibiting Th17 differentiation and inducing the conversion of effector T cells into IL-10-producing T regulatory type I-like (Tr1-like) cells. This functional dichotomy suggests that IL-27 may play a critical role in regulating the delicate balance between pro- and anti-inflammatory signaling. Additionally, IL-27 promotes the survival and function of T follicular helper cells and enhances the functions of germinal center B cells.

Unlike other IL-12 family members, IL-35 seems to function solely as an anti-inflammatory cytokine. It enhances regulatory T cell proliferation, suppresses the proliferation of conventional T cells, and induces the conversion of naïve conventional T cells into IL-35-producing induced regulatory T cells (iTr35 cells). Additionally, it promotes the conversion of B cells into IL-10-, IL-35-producing regulatory B cells. As a result, IL-35 has been suggested to be involved in inhibiting the pathogenesis of autoimmune and inflammatory diseases.

Although only a few studies have been published on IL-39 to date, its observed activities suggest that it has pro-inflammatory effects. IL-39 has been shown to induce neutrophil expansion or differentiation and to stimulate BAFF production by these cells, which has been implicated in the pathophysiology of systemic lupus erythematosus (SLE) and other autoimmune diseases. IL-39 has also been found to be secreted by keratinocytes, but whether it has protective or pathogenic effects in the skin awaits further investigation.

To learn more, please visit our IL-12 Family Research Area.

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