Cong-Qiu Chu - Targeting the IL-17 Pathway in Inflammatory Disorders

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Springer International Publishing Switzerland 2017

Cong-Qiu Chu Targeting the IL-17 Pathway in Inflammatory Disorders 10.1007/978-3-319-28040-0_1

1. Overview of IL-17 Family

Cong-Qiu Chu 1

(1)

VA Portland Health Care System, Oregon Health & Science University, Portland, Oregon, USA

1.1 Discovery and Structure of IL-17

The name of IL-17 was first proposed by Yao et al. [].

IL-17E was found to be identical to IL-25, which was described by an independent group [].

1.2 IL-17 Receptors and Signaling

IL-17 receptor (IL-17R) is also a unique cytokine receptor family [].

Figure 1.1

IL-17 receptors. The IL-17R family comprises five members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. IL-17RA is a common receptor that forms heterodimers with other IL-17Rs for ligand binding and signal transduction: IL-17RA-RC for IL-17A, IL-17F, and IL-17A/F; IL-17RA-RE for IL-17C; IL-17RA-RB for IL-17E (IL-25). It is not clear whether IL-17RB also forms a homodimer for IL-17B; IL-17RD remains an orphan receptor, but it regulates IL-17A signaling and forms TNFR2IL-17RD receptor complex. The receptor for IL-17D has not been identified. IL-17RA-RC, IL-17RA-RB, and IL-17RA-RE transduce signal via adaptor molecule Act1. Act1 NFB activator 1 (also known as CIKS connection to IKK and SAPK/JNK), IL-17RA IL-17 receptor adaptor, C/EBPs CCAAT-enhancer-binding proteins, MAPKs mitogen-activated protein kinases, NFB nuclear factor B, TRAF tumor necrosis factor-associated factor

Indeed, the major IL-17RA interacting residues are identical among all IL-17 cytokines [].

The proinflammatory and host defense effects of IL-17A and IL-17F are executed chiefly by activation of NFB and MAPK pathways. A signal from IL-17R is first relayed by a cytosolic protein, signaling adaptor, called Act1 (NFB activator 1, also known as CIKS) (Fig. ].

Figure 1.2

Structure of Act1. Act1 is IL-17R adaptor which relays IL-17 cytokineIL-17R signaling. It contains a SEFIR domain that binds cytoplasmic SEFIR domain of IL-17Rs. A decoy peptide correspondence of the sequence of CC loop of Act1 SEFIR domain can block the IL-17A and IL-17E (IL-25) signaling, indicating interruption of interaction between Act1 and IL-17R is potentially therapeutic. C/EBP CCAAT-enhancer-binding proteins, HLH helixloophelix, MAPKs mitogen-activated protein kinases, NFB nuclear factor B, SEFIR similar expression to fibroblast growth factor genes and IL-17R, TRAF tumor necrosis factor-associated factor

Act1 is essential for IL-17 signal transduction. Deficiency of Act1 results in a loss of IL-17-dependent NFB activation and proinflammatory cytokine production [].

The importance of Act1 in autoimmunity and inflammatory diseases has been demonstrated in animal models of inflammatory diseases. For instance, mice with deficiency of Act1 have reduced demyelination in a cuprizone-induced multiple sclerosis (MS) model, which is known to be mediated by IL-17 signaling []. These data suggest that Act1 is a candidate target for therapeutic intervention in human inflammatory diseases.

As in other cytokine signaling, IL-17/IL-17R signaling is also finely regulated. Many regulators have been described to involve positive and negative regulation of the IL-17/IL-17R signaling pathway at various stages []. These soluble receptor-Fc fusion proteins are highly likely to be evaluated as therapeutic agents (Fig. 5.1b).

Signaling through the IL-17R complex can influence function of other IL-17 cytokines. Chang et al. []. These findings indicate that IL-17C may be another target for therapy in Th17-mediated inflammatory diseases, but caution needs to be taken for its protective effect in intestines.

It is noteworthy that IL-17RD remains an orphan receptor, i.e., no ligand has been identified to bind IL-17RD. Interestingly, IL-17RD is able to critically regulate the activities of IL-17A [].

Recent studies also revealed that IL-17RD negatively regulates TLR response []. These data indicate a complex regulatory mechanism that IL-17RD is involved with other inflammatory pathways.

References

Yao Z, Fanslow WC, Seldin MF, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995;3:81121. CrossRef PubMed

Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol. 1993;150:544556. PubMed

Yao Z, Painter SL, Fanslow WC, et al. Human IL-17: a novel cytokine derived from T cells. J Immunol. 1995;155:54836. PubMed

Lee J, Ho WH, Maruoka M, et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem. 2001;276:16604. CrossRef PubMed

Li H, Chen J, Huang A, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A. 2000;97:7738. CrossRef PubMed PubMedCentral

Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol. 2002;169:6426. CrossRef PubMed

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Kramer JM, Hanel W, Shen F, et al. Cutting edge: identification of a pre-ligand assembly domain (PLAD) and ligand binding site in the IL-17 receptor. J Immunol. 2007;179:637983. CrossRef PubMed PubMedCentral

Ely LK, Fischer S, Garcia KC. Structural basis of receptor sharing by interleukin 17 cytokines. Nat Immunol. 2009;10:124551. CrossRef PubMed PubMedCentral

Chang SH, Reynolds JM, Pappu BP, et al. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity. 2011;35:61121. CrossRef PubMed

Song X, Zhu S, Shi P, et al. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol. 2011;12:11518. CrossRef PubMed

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