IL-23/Th17 axis is not influenced by TNF-blocking agents in ankylosing spondylitis patients

Milanez, Fernanda Manente; Saad, Carla Gonçalves Schahin; Viana, Vilma T; Moraes, José Reinaldo da Silva Cabral de; Périco, Grégory Vinícius; Sampaio-Barros, Percival D.; Gonçalves, Célio Roberto; Bonfá, Eloísa

doi:10.1186/s13075-016-0949-6

Cited by 38 publications

(29 citation statements)

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“…However, we found no direct correlation between Th17 cell frequencies and disease activity as defined by the BASDAI score. A lack of correlation has been previously reported by some research groups [11,15,52]. In contrast, other researchers found a correlation between BASDAI scores and Th17 cell frequencies or IL-17 levels in the serum [13,18].…”

Section: Discussionmentioning

confidence: 74%

“…Moreover, EP2 and EP4 differentially regulate IL-17A and IL-17F secretion by Th17 cells [51]. Interestingly, PGE 2 levels are increased in the peripheral blood of patients with high disease activity but not in the blood of patients with low disease activity [52]. Compared to AS, EP4 plays a less significant role in Th17 cell induction in RA (Additional file 2: Figure S2b).…”

Section: Discussionmentioning

confidence: 99%

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Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

et al. 2019

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Background: Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). However, the mechanism underlying enhanced Th17 cell accumulation in AS remains unknown. The prostaglandin E 2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Interestingly, recent genomewide association studies (GWAS) have identified five risk alleles for AS in PTGER4, the gene encoding for EP4. The aim of this study was to reveal a possible link between EP4 and disease activity in patients with AS. Methods: Th17 cells from patients with AS were analyzed for the transcriptional expression of prostaglandin receptor genes by quantitative RT-PCR. Th17 cells from patients with rheumatoid arthritis (RA) and from healthy individuals served as controls. EP4 receptor expression in Th17 cells was assessed ex vivo by flow cytometry and by western blot. Functional analysis using EP4-specific agonists was performed to reveal how EP4 regulates Th17 cells. Results: EP4 is significantly overexpressed in Th17 cells from patients with AS compared to Th17 cells from healthy individuals or patients with RA or psoriatic arthritis (PsA). EP4 upregulation is unique to Th17 cells and is not found in other CD4 + T cell subsets. Specific activation of EP4 drives Th17 cell development and promotes EP4 expression in a positive feedback loop in AS but not in RA or PsA. Mechanistically, EP4 acts via upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORγt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. Increased EP4 expression levels in Th17 cells from AS patients correlate with high disease activity as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 (r = 0.7591, p = 0.0016). Conclusions: EP4 is a potential marker of disease activity in patients with AS. Aberrant EP4 expression might contribute to pathogenic Th17 cell accumulation and represent a new target for the treatment of AS.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

et al. 2019

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“…Indeed, corticosteroids and TNF-α inhibitors may potentially modulate the number of Th17 cells and the levels of circulating IL-17A ( 19 ). On the contrary, a previous work has shown that the IL-23/Th17 axis is not influenced by TNF inhibitors, since after 24-month administration of these agents in patients with AS, IL-23 remained unchanged and stayed elevated while in parallel a clinical improvement was observed ( 20 ). In addition, in the study by Hayashi et al ( 11 ), 15 of 30 patients with AS received a TNF inhibitor, but MAIT cell frequency or IL-17A production by MAIT cells did not differ between patients who received the biological agent and those who did not.…”

Section: Discussionmentioning

confidence: 86%

Increased IL-22- and IL-17A-Producing Mucosal-Associated Invariant T Cells in the Peripheral Blood of Patients With Ankylosing Spondylitis

et al. 2018

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The IL-23/T helper 17 (Th17) axis plays an important role in joint inflammation in ankylosing spondylitis (AS). Conventional CD4+ Th17 cells are a major source of IL-17A. IL-22 is another cytokine implicated in AS pathophysiology and is produced by Th17 and Th22 cells. In this study, we aimed to analyze conventional and non-conventional T cell subsets producing IL-17A and IL-22 in patients with AS. We thus evaluated the intracellular staining for IL-17A, IL-22, and IFN-γ in peripheral blood mononuclear cells of 36 patients with AS and 55 age- and sex-matched healthy controls (HC). Conventional CD4+ and CD8+ T cells, γδ T cells, and mucosal-associated invariant T (MAIT) cells were evaluated. In patients with AS, we found a decreased frequency and number of γδ T cells, of MAIT cells and of IFN-γ+ CD4+ and CD8+ T cells. Th17-related IL-17A+/IFN-γ− CD4+ T cells were decreased in AS. The number of IL-22+ MAIT cells was higher in AS compared with HC, as well as the number of IFN-γ+/IL-17A+ MAIT cells. The number of IFN-γ−/IL-17A+ MAIT cells was higher only in female patients with AS compared with female HC. The cellular source of IL-17A was thus not restricted to conventional Th17 CD4+ T cells and might involve innate-like T cells, such as MAIT cells. Circulating MAIT cells producing IL-22 were increased in AS. These results strengthen the importance of innate and innate-like sources of IL-17A and/or IL-22.

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“…Anti-TNF therapy was associated with increased expression levels of miR-7114-5p. Milanez et al found that the use of anti-TNF therapy in patients with AS did not affect the plasma level of IL-23 [ 28 ]. The use of anti-TNF therapy might indicate that these patients with AS had more severe or more active disease.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis

Lai

Tung

et al. 2018

Arthritis Res Ther

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BackgroundInterleukin (IL)-23 can facilitate the differentiation of IL-17-producing helper T cells (Th17). The IL-23/IL-17 axis is known to play a key role in the immunopathogenesis of ankylosing spondylitis (AS). We hypothesized that the expression of microRNAs (miRNAs, miRs) would be regulated by IL-23 and that these miRNAs could participate in the immunopathogenesis of AS.MethodsExpression profiles of human miRNAs in K562 cells, cultured in the presence or absence of IL-23 for 3 days, were analyzed by microarray. Potentially aberrantly expressed miRNAs were validated using T-cell samples from 24 patients with AS and 16 control subjects. Next-generation sequencing (NGS) was conducted to search for gene expression and biological functions regulated by specific miRNAs in the IL-23-mediated signaling pathway.ResultsInitial analysis revealed that the expression levels of 12 miRNAs were significantly higher, whereas those of 4 miRNAs were significantly lower, in K562 cells after coculture with IL-23 for 3 days. Among these IL-23-regulated miRNAs, the expression levels of miR-29b-1-5p, miR-4449, miR-211-3p, miR-1914-3p, and miR-7114-5p were found to be higher in AS T cells. The transfection of miR-29b-1-5p mimic suppressed IL-23-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation in K562 cells. After NGS analysis and validation, we found that miR-29b-1-5p upregulated the expression of angiogenin, which was also upregulated in K562 cells after coculture with IL-23. Increased expression of miR-29b-1-5p or miR-211-3p could enhance interferon-γ expression.ConclusionsAmong the miRNAs regulated by IL-23, expression levels of five miRNAs were increased in T cells from patients with AS. The transfection of miR-29b-1-5p mimic could inhibit the IL-23-mediated STAT3 phosphorylation and might play a role in negative feedback control in the immunopathogenesis of AS.

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IL-23/Th17 axis is not influenced by TNF-blocking agents in ankylosing spondylitis patients

Cited by 38 publications

References 50 publications

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

Increased IL-22- and IL-17A-Producing Mucosal-Associated Invariant T Cells in the Peripheral Blood of Patients With Ankylosing Spondylitis

Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis

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