Cutting Edge: Interleukin 17 Signals through a Heteromeric Receptor Complex

Toy, Dean; Kugler, David; Wolfson, Martin F.; Bos, Tim Vanden; Gurgel, Jesse L.; Derry, Jonathan M.J.; Tocker, Joel; Peschon, Jacques J.

doi:10.4049/jimmunol.177.1.36

Cited by 501 publications

(441 citation statements)

References 30 publications

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“…Receptors of IL-17 make up a distinct family of cytokine receptors (31). IL-17A binds to its receptors, IL-17RA and IL-17RC, to activate downstream signal transduction (32,33). Our RT-PCR results indicated that both EPCs and PMVECs expressed higher mRNA levels of IL-17RA and IL-17RC compared with human FIGURE 9.…”

Section: Discussionmentioning

confidence: 70%

IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

Gao

et al. 2015

The Journal of Immunology

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We previously demonstrated an essential role of Th17 cells in excessive mucous secretion and airway smooth muscle proliferation in a prolonged OVA-challenged C57BL/6 mouse model. However, the impact of Th17 cells in vascular remodeling, another characteristic feature of airway remodeling in asthma, remains elusive. This issue was further investigated in this study. The time-course experiments showed that progressively increasing levels of Th17 cells and IL-17A (not IL-17F) in the lungs of prolonged allergen-challenged mice were positively correlated with microvessel density in peribronchial tissues. In addition, exaggerated airway vascular remodeling in this mouse model was exacerbated by airway administration of IL-17A or adoptive transfer of Th17 cells. This effect was dramatically alleviated by the administration of anti–IL-17A Ab, but not anti–IL-17F Ab. Boyden chamber assays indicated that IL-17A accelerates endothelial progenitor cell (EPC) migration. Furthermore, EPC accumulation in the airways of allergen-exposed mice after adoptive transfer of Th17 cells was eliminated by blockade of IL-17A. We found that IL-17A promoted tubule-like formation rather than proliferation of pulmonary microvascular endothelia cells (PMVECs) in vitro. In addition, IL-17A induced PMVEC tube formation via the PI3K/AKT1 pathway, and suppression of the PI3K pathway markedly reduced the formation of tubule-like structures. Collectively, our results indicate that Th17 cells contribute to the airway vascular remodeling in asthma by mediating EPC chemotaxis, as well as PMVEC tube formation, via IL-17A rather than IL-17F.

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Section: Discussionmentioning

confidence: 70%

IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

Gao

et al. 2015

The Journal of Immunology

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“…IL-17 mediates inflammation and tissue destruction through a receptor (IL-17R) composed of two subunits, IL-17RA and IL-17RC [45]. The IL-17R is a type I transmembrane protein with no sequence similarity with any other known cytokine receptor [5].…”

Section: What Is the Most Physiologically Relevant Target Of Il-17a Imentioning

confidence: 99%

IL-17/Th17 targeting: On the road to prevent chronic destructive arthritis?

Lubberts¹

2008

Cytokine

269

230

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Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis. Data from experimental arthritis indicate IL-17 receptor signaling as a critical pathway in turning an acute synovitis into a chronic destructive arthritis. The identification of six IL-17 family members (IL-17A-F) may extend the role of this novel cytokine family in the pathogenesis of chronic destructive joint inflammation. Whether the successful anti-IL-17A cytokine therapy in murine arthritis can be effectively translated to human arthritis need to be tested in clinical trials in humans. Interestingly, IL-17A and IL-17F are secreted by the novel T helper subset named Th17. This novel pathogenic T cell population induces autoimmune inflammation in mice and is far more efficient at inducing Th1-mediated autoimmune inflammation in mice than classical Th1 cells (IFN-c). In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26. Th17 cells have been established as a separate lineage of T helper cells in mice distinct from conventional Th1 and Th2 cells. Whether this also applies to human Th17 and whether RA is a Th1 or a Th17 mediated disease is still not clear. This review summarizes the findings about the role of IL-17 in arthritis and discusses the impact of the discovery of the novel Th17 cells for arthritis. Further studies are needed to unravel the role of Th17 cells and the interplay of IL-17 and other Th17 cytokines in the pathogenesis of arthritis and whether regulating Th17 cell activity will have additional value compared to neutralizing IL-17A activity alone. This might help to reach the ultimate goal not only to treat RA patients but to prevent the development of this crippling disease.

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“…Recently, it was reported that IL-17RA might form a heterodimer with IL-17RC [10]. IL-17 activates NFkB and MAP kinase pathways, which results in the up-regulation of IL-6 [11,12].…”

Section: Introductionmentioning

confidence: 99%