Functional Specialization of Interleukin-17 Family Members

Laboratory of Molecular Pathogenesis, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.
Immunity (Impact Factor: 21.56). 02/2011; 34(2):149-62. DOI: 10.1016/j.immuni.2011.02.012
Source: PubMed


Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.

Download full-text


Available from: Yoichiro Iwakura,
    • "These data indicate that IL-17A may mediate the bone catabolic activity of cPTH by upregulating the production of RANKL by osteocytes and osteoblasts. IL-17A binds to the heterodimeric receptor IL-17RA/IL-17RC, known as IL-17RA (Iwakura et al., 2011; Zepp et al., 2011). IL- 17A signaling is silenced in IL-17RA À/À mice (Ye et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF), which increases the differentiation of IL-17A-producing Th17 cells via TNF receptor 1 (TNFR1) signaling in CD4(+) cells. Moreover, cPTH enhances the sensitivity of naive CD4(+) cells to TNF via GαS/cAMP/Ca(2+) signaling. Accordingly, conditional deletion of GαS in CD4(+) cells and treatment with the calcium channel blocker diltiazem prevents Th17 cell expansion and blocks cPTH-induced bone loss. Neutralization of IL-17A and calcium channel blockers may thus represent novel therapeutic strategies for hyperparathyroidism.
    Cell metabolism 10/2015; DOI:10.1016/j.cmet.2015.09.012 · 17.57 Impact Factor
    • "An association between IL-17 and asthma has also been previously demonstrated as indicated in studies showing that local production of IL-17 was increased in asthmatic airways and its concentration in the sputum was correlated with bronchial hyper-responsiveness (Barczyk et al., 2003; Bettelli et al., 2007). Several studies have demonstrated that patients with severe asthma have a marked increase in IL-17 levels in lung biopsy specimens, which was also associated with disease severity (Cosmi et al., 2011; Hashimoto et al., 2005; Iwakura et al., 2011). Such findings suggest that Th17 cells are important in the etiology of asthma and that the increased production of IL-17 by peripheral blood cells from ASD children with asthma in the current study further supports this notion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation and asthma have both been reported in some children with autism spectrum disorder (ASD). To further assess this connection, peripheral immune cells isolated from young children with ASD and typically developing (TD) controls and the production of cytokines IL-17, -13, and -4 assessed following ex vivo mitogen stimulation. Notably, IL-17 production was significantly higher following stimulation in ASD children compared to controls. Moreover, IL-17 was increased in ASD children with co-morbid asthma compared to controls with the same condition. In conclusion, children with ASD exhibited a differential response to T cell stimulation with elevated IL-17 production compared to controls. Copyright © 2015. Published by Elsevier B.V.
    Journal of neuroimmunology 09/2015; 286:33-41. DOI:10.1016/j.jneuroim.2015.07.003 · 2.47 Impact Factor
  • Source
    • "endent manner ( Stoolman et al . , 2014 ) . In classical EAE in WT mice , CCL2 was increased in the spinal cord driving the recruitment of monocytes / macrophages in a partially CCR2 - dependent manner ( Stoolman et al . , 2014 ) . Given that IL - 17 induces CXCL2 the conclusion that atypical EAE was IL - 17 - independent is an important finding ( Iwakura et al . , 2011 ; Stoolman et al . , 2014 ) . In the Goverman study using C3HeB / FeJ mice deficient in either IFNGR or IL - 17RA , it was shown that IL - 17 promoted ELR + CXC chemokine - mediated recruitment of neutrophils into the brain while IFN - γ inhibited ELR + CXC chemokine and neutrophil production in the brain , but had the converse effect i"
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by T helper (h)1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-γ administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), indicated that IFN-γ exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-γ or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-γ in the CNS. In particular, they revealed that IFN-γ is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB) and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on strong EAE data this view is being reevaluated by some investigators in the field.
    Frontiers in Neuroscience 09/2015; 9:287. DOI:10.3389/fnins.2015.00287 · 3.66 Impact Factor
Show more