Interleukin-17: a mediator of inflammatory responses

Witowski, Janusz; Książek, Krzysztof; Jörres, Achim

doi:10.1007/s00018-003-3228-z

Cited by 224 publications

(176 citation statements)

References 100 publications

(176 reference statements)

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“…They show the same gene organization of the human IL-17A/F, formed with two introns and three exons, differing in the length of the introns which are longer in human IL-17A/F. Sequence alignments showed four cysteins strictly conserved in regions that in human IL-17A and F are correspondent to functionally and structurally essential motifs (Witowski et al, 2004). The three-dimensional structure model, made on the basis of the crystal structure of human IL-17F, displays the cysteines localized in β-sheets, and supported the preservation of the disulphide linkages position in all the IL-17 homologs (Hymowitz et al, 2001).…”

Section: Discussionmentioning

confidence: 71%

Ciona intestinalis interleukin 17-like genes expression is upregulated by LPS challenge

Vizzini

Falco

Parrinello

et al. 2015

Developmental & Comparative Immunology

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Section: Discussionmentioning

confidence: 71%

Ciona intestinalis interleukin 17-like genes expression is upregulated by LPS challenge

Vizzini

Falco

Parrinello

et al. 2015

Developmental & Comparative Immunology

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“…Neutralization of IL-17A has strong pre-clinical and clinical target validation and documentation of efficacy in a proof of concept study (CAIN457A2101) and a phase II study (CAIN457F2201) in Rheumatoid Arthritis (RA). IL-17A has been shown to play a pivotal direct pathogenetic role in both inflammatory and destructive joint tissue manifestations of RA and has direct effects on matrix metalloprotease (MMP) activation and stimulation of osteoclast-mediated bone resorption (Stamp 2004;Witowski 2004;Moseley 2003). Interim analysis of all 42 subjects enrolled in the PsA PoC study CAIN457A2206 who completed week 6, together with preliminary data from the later time points up to week 16, suggest that a clinically meaningful response for signs and symptoms is induced as early as 2 weeks after start of secukinumab treatment, with further improvement up to week 6 and maintenance of response up to week 16.…”

Section: Introductionmentioning

confidence: 99%

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis

et al. 2015

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A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the long term safety, tolerability and efficacy up to 2 years in patients with active psoriatic arthritis List of tables List of figures Glossary of termsAssessment A procedure used to generate data required by the study Control drug A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug Enrollment Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e. prior to starting any of the procedures described in the protocol)Inadequate response to TNFα Active disease despite stable treatment with anti-TNFa for at least 3 months at a stable dose or for at least one dose in the case of lack of tolerance Investigational drugThe study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3 and is synonymous with "investigational new drug."Medication number A unique identifier on the label of each study drug package in studies that dispense study drug using an IVR systemPatient number A number assigned to each patient who enrolls in the study. When combined with the center number, a unique identifier is created for each patient in the study. PeriodA minor subdivision of the study timeline; divides phases into smaller functional segments such as screening, baseline, titration, washout, etc.Phase A major subdivision of the study timeline; begins and ends with major study milestones such as enrollment, randomization, completion of treatment, etc.Premature patient withdrawal Point/time when the patient exits from the study prior to the planned completion of all study drug administration and assessments; at this time all study drug administration is discontinued and no further assessments are plannedRandomization number A unique identifier assigned to each randomized patient, corresponding to a specific treatment arm assignment Stop study participation Point/time at which the patient came in for a final evaluation visit or when study drug was discontinued whichever is later Study drug Any drug administered to the patient as part of the required study procedures; includes investigational drug and any control drugs Study drug discontinuation Point/time when patient permanently stops taking study drug for any reason; may or may not also be the point/time of premature patient withdrawal Variable Information used in the data analysis; derived directly or indirectly from data collected using specified assessments at specified timepointsThis document (090095a88362b521 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI. Protocol synopsisTitle of study: A randomized, double-blind, placebo-controlled, multicenter study of secukinumab to demonstrate the efficacy at 24 weeks and to assess the safety, tolerability and...

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“…It has been shown by reverse transcriptase-PCR experiments that the cytokines are expressed in activated human CD4ϩ T cells (11,12). Expression of IL-17F and IL-17A has also been observed in tissue samples from various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and asthma (2,3,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

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confidence: 99%

Identification of an Interleukin 17F/17A Heterodimer in Activated Human CD4+ T Cells

Wright

Guo²,

Quazi

et al. 2007

Journal of Biological Chemistry

291

232

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IL-17F and IL-17A are members of the IL-17 pro-inflammatory cytokine family. IL-17A has been implicated in the pathogenesis of autoimmune diseases. IL-17F is a disulfidelinked dimer that contains a cysteine-knot motif. We hypothesized that IL-17F and IL-17A could form a heterodimer due to their sequence homology and overlapping pattern of expression. We evaluated the structure of recombinant IL-17F and IL-17A proteins, as well as that of natural IL-17F and IL-17A derived from activated human CD4؉ T cells, by enzyme-linked immunosorbent assay, immunoprecipitation followed by Western blotting, and mass spectrometry. We find that both IL-17F and IL-17A can form both homodimeric and heterodimeric proteins when expressed in a recombinant system, and that all forms of the recombinant proteins have in vitro functional activity. Furthermore, we find that in addition to the homodimers of IL-17F and IL-17A, activated human CD4؉ T cells also produce the IL-17F/IL-17A heterodimer. These data suggest that the IL-17F/IL-17A heterodimer may contribute to the T cell-mediated immune responses.Interleukins 17F 3 and 17A (IL-17A) are closely related members of the IL-17 cytokine family, and share 50% amino acid identity. Studies in the mouse have identified Th17 cells as a distinct CD4ϩ T cell lineage that is defined by the production of IL-17F and IL-17A (1-7). IL-6 and transforming growth factor-␤ (TGF-␤) are required for the differentiation of naïve CD4ϩ T cells to Th17 cells (1,8), which are maintained in the presence of IL-23 and IL-1␤. Conversely, IL-4 and interferon-␥ can inhibit the development of Th17 cells (9, 10). Th17 cells have been implicated in the pathology of mouse autoimmune disease models (2).Expression of IL-17F and IL-17A has been detected in activated human peripheral blood lymphocytes. It has been shown by reverse transcriptase-PCR experiments that the cytokines are expressed in activated human CD4ϩ T cells (11,12). Expression of IL-17F and IL-17A has also been observed in tissue samples from various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and asthma (2, 3, 13-22).The crystal structure of IL-17F has been solved and shows that the protein forms a disulfide-linked dimeric glycoprotein (23). IL-17A is also a disulfide-linked homodimeric glycoprotein (24), although crystal structure or data defining the precise subunit interactions are lacking. The IL-17F homodimer includes a classical cysteine knot motif, which is found in the TGF-␤, bone morphogenetic protein, and nerve growth factor superfamilies (25, 26). One difference in the cysteine knot motif of IL-17F compared with the other known cysteine knot protein families is that it only utilizes four cysteines instead of the classical six cysteines to form the knot.There have been reports that some of the cysteine knot family members can exist as heterodimers in vivo. TGF-␤1.2 and -␤2.3 were identified in bovine bone extracts, whereas inhibin and activin AB have been found in gonadal fluids (27...

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Interleukin-17: a mediator of inflammatory responses

Cited by 224 publications

References 100 publications

Ciona intestinalis interleukin 17-like genes expression is upregulated by LPS challenge

Ciona intestinalis interleukin 17-like genes expression is upregulated by LPS challenge

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis

Identification of an Interleukin 17F/17A Heterodimer in Activated Human CD4+ T Cells

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