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Cited by 142Cytokine Signaling Pathways and InteractionsT-cell and B-cell ImmunologyPsoriasis: Treatment and Pathogenesis

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Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family

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Hasegawa, Hideaki, Mizoguchi, Izuru, Chiba, Yukino, Ohashi, Mio, Xu, Mingli, Yoshimoto, Takayuki·2016·Frontiers in Immunology
DOI 10.3389/fimmu.2016.00479PMC PMC5095122
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Abstract

The interleukin (IL)-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics in that they are composed of two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing; currently, there are more than 6 cytokines, including the tentatively named cytokines IL-Y (p28/p40), IL-12 (p35/p40), IL-23 (p19/p40), IL-27 [p28/Epstein-Barr virus-induced protein 3 (EBI3)], IL-35 (p35/EBI3), and IL-39 (p19/EBI3). This family of cytokines covers a very broad range of immune responses, including pro-inflammatory responses such as helper T (Th)1, Th2, and Th17 to anti-inflammatory responses such as regulatory T (Treg) cells and IL-10-producing Treg cells. IL-12 is the first member of this family, and IL-12, IL-23, and IL-27 are mainly produced by activated antigen-presenting cells such as dendritic cells and macrophages. IL-12 plays a critical role in the promotion of Th1 immune responses by inducing interferon-γ production to combat pathogens and malignant tumors. IL-23 induces IL-17 production and is necessary to maintain pathogenic Th17 cells that cause inflammatory and autoimmune diseases. IL-27 was initially reported to play a critical role in promotion of Th1 differentiation; however, subsequent studies revealed that IL-27 has broader stimulatory and inhibitory roles by inducing IL-10-producing Treg cells. IL-35 is produced by forkhead box P3+ Treg cells and activated B cells and has immunosuppressive functions to maintain immune tolerance. The most recently identified cytokine, IL-39, is produced by activated B cells and has pro-inflammatory functions. The cytokine tentatively named IL-Y seems to have anti-inflammatory functions by inhibiting Th1 and Th17 differentiation. In addition, individual cytokine subunits were also shown to have self-standing activities. Thus, promiscuity within the IL-6/IL-12 family cytokines complicates structural and functional clarification and assignment of individual cytokines. A better understanding of the recent advances and expanding diversity in molecular structures and functions of the IL-6/IL-12 family cytokines could allow the creation of novel therapeutic strategies by using them as tools and targeted molecules.

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Figure 1 The IL-6/IL-12 family cytokines. The IL-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics, because they are composed of two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing. Currently, there are more than six cytokines, including tentatively named cytokines.
Figure 1 The IL-6/IL-12 family cytokines. The IL-6/IL-12 family cytokines have pleiotropic functions and play critical roles in multiple immune responses. This cytokine family has very unique characteristics, because they are composed of two distinct subunits forming a heterodimer and each cytokine and receptor subunit shares with each other. The members of this cytokine family are increasing. Currently, there are more than six cytokines, including tentatively named cytokines.CC BY · PubMed Central
Figure 2 Recent advances in molecular structures and functions of the IL-6/IL-12 family cytokines. Promiscuity within the IL-6/IL-12 family cytokines complicates the structural and functional clarification and assignment of individual cytokines. The roles of this family of cytokines are expanding, and individual cytokine subunits have been shown to have self-standing activities. This illustrates the recent advances in molecular structures and functions of the IL-6/IL-12 family cytokines. Up-arrow in blue and down-arrow in red mean upregulation and downregulation of expression, respectively. Breg, regulatory B; CCl4, carbon tetrachloride; CLF, cytokine-like factor 1; Con A, concanavalin A; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; EAU, experimental autoimmune uveitis; HSC, hematopoietic stem cell; ICAM-1, intracellular adhesion molecule-1; LPS, lipopolysaccharide; MΦ, macrophage; NOD, non-obese diabetic; TLR, toll-like receptor; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule-1.
Figure 2 Recent advances in molecular structures and functions of the IL-6/IL-12 family cytokines. Promiscuity within the IL-6/IL-12 family cytokines complicates the structural and functional clarification and assignment of individual cytokines. The roles of this family of cytokines are expanding, and individual cytokine subunits have been shown to have self-standing activities. This illustrates the recent advances in molecular structures and functions of the IL-6/IL-12 family cytokines. Up-arrow in blue and down-arrow in red mean upregulation and downregulation of expression, respectively. Breg, regulatory B; CCl4, carbon tetrachloride; CLF, cytokine-like factor 1; Con A, concanavalin A; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; EAU, experimental autoimmune uveitis; HSC, hematopoietic stem cell; ICAM-1, intracellular adhesion molecule-1; LPS, lipopolysaccharide; MΦ, macrophage; NOD, non-obese diabetic; TLR, toll-like receptor; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule-1.CC BY · PubMed Central
Figure 3 IL-35 and the composition of its receptor subunits. IL-35, a heterodimeric cytokine of p35 and EBI3, is preferentially secreted by forkhead box P3 (Foxp3+) Treg cells and induces IL-35-producing Treg (iTR35) cells with immunosuppressive activity. The receptor for IL-35 is a heterodimer of gp130 and IL-12Rβ2, and it signals via activation of a heterodimer of STAT1 and STAT4. In addition, IL-35 also has the ability to mediate signaling in the presence of only one of them as a homodimer. IL-35 also produced from CD19+CD138hi B cells induces the expansion of B regulatory (Breg) cells producing IL-35 and, intriguingly, activates a heterodimer of STAT1 and STAT3 through the IL-35 receptor comprising IL-12Rβ2 and WSX-1.
Figure 3 IL-35 and the composition of its receptor subunits. IL-35, a heterodimeric cytokine of p35 and EBI3, is preferentially secreted by forkhead box P3 (Foxp3+) Treg cells and induces IL-35-producing Treg (iTR35) cells with immunosuppressive activity. The receptor for IL-35 is a heterodimer of gp130 and IL-12Rβ2, and it signals via activation of a heterodimer of STAT1 and STAT4. In addition, IL-35 also has the ability to mediate signaling in the presence of only one of them as a homodimer. IL-35 also produced from CD19+CD138hi B cells induces the expansion of B regulatory (Breg) cells producing IL-35 and, intriguingly, activates a heterodimer of STAT1 and STAT3 through the IL-35 receptor comprising IL-12Rβ2 and WSX-1.CC BY · PubMed Central
Figure 4 IL-30 and its related molecules. IL-6 is unique in signaling through not only membrane-bound IL-6Rα but also sIL-6Rα. The former is called IL-6 classic signaling through membrane-bound IL-6Rα together with gp130, and the latter is called IL-6 trans-signaling by IL-6 bound with sIL-6Rα and IL-6/sIL-6Rα (also designated Hyper-IL-6) through only gp130. The α subunit of IL-27, p28, which is referred to as IL-30, functions as an agonistic cytokine via the gp130 signaling pathway similar to IL-6, either by itself or associating with other molecules such as IL-12p40, CLF, IL-6Rα, forming p28/IL-6Rα classic signaling, p28/sIL-6Rα trans-signaling, and p28 signaling. Moreover, p28 can activate signal transduction via gp130, even in the absence of IL-6Rα or EBI3, albeit at higher concentrations.
Figure 4 IL-30 and its related molecules. IL-6 is unique in signaling through not only membrane-bound IL-6Rα but also sIL-6Rα. The former is called IL-6 classic signaling through membrane-bound IL-6Rα together with gp130, and the latter is called IL-6 trans-signaling by IL-6 bound with sIL-6Rα and IL-6/sIL-6Rα (also designated Hyper-IL-6) through only gp130. The α subunit of IL-27, p28, which is referred to as IL-30, functions as an agonistic cytokine via the gp130 signaling pathway similar to IL-6, either by itself or associating with other molecules such as IL-12p40, CLF, IL-6Rα, forming p28/IL-6Rα classic signaling, p28/sIL-6Rα trans-signaling, and p28 signaling. Moreover, p28 can activate signal transduction via gp130, even in the absence of IL-6Rα or EBI3, albeit at higher concentrations.CC BY · PubMed Central

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Metadata

Authors
Hasegawa, H., Mizoguchi, I., Chiba, Y., Ohashi, M., Xu, M., & Yoshimoto, T.
Affiliations
Tokyo Medical University (JP)
Corresponding author
Yoshimoto, Takayuki
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2016-11-04
Volume
7
Pages
479-479
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2016.00479
PMC
PMC5095122
OpenAlex
W2548333195
Cited by
142
References
79
Citations by year
2026: 6 · 2025: 13 · 2024: 16 · 2023: 14 · 2022: 13 · 2021: 16 · 2020: 16 · 2019: 17 · 2018: 22 · 2017: 9
FWCI
1.61
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Japan Society for the Promotion of Science (16J04160, 15K07947, 15K08433)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
heterodimeric cytokine, IL-12, IL-23, IL-27, IL-35, IL-39, p40 subunit, EBI3, Th1 cells, Th17 cells, regulatory T cells, IL-10, interferon-gamma, IL-17, dendritic cells, macrophages

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