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We read with great interest the article by Gao et al.1 They have reported the regulatory role of the JAK/STAT kinase system on the inflammatory/proliferative cascades for pannus formation in psoriatic arthritis (PsA) such as on fibroblast like synovial cells (FLS) biology and on secretion of inflammatory cytokines (interleukin (IL) 6, IL-8, monocyte chemoattractant protein (MCP)-1) by these FLS. Tofacitinib targets JAK1 and JAK2 with IC50 values in the same order of magnitude as that of JAK3.2 They have also provided the mechanisms of actions of tofacitinib by demonstrating that tofacitinib significantly decreased pSTAT3, pSTAT1, NFκBp65 in PsAFLS and inhibits the cellular and molecular events of pannus formation. However, Gao et al did not address a critical issue whether JAK/STAT signalling system regulates the IL-23/IL-17 cytokine axis in PsA. Here we are sharing an alternative mechanism for the role of JAK/STAT kinase system in the pathogenesis of PsA.
Aberrant activation of IL-23/IL-17 cytokine axis is a dominant pathology in PsA.3 ,4 JAK2 is recruited to IL-23 receptor, so it is expected that JAK/STAT-mediated signalling system is important in PsA. We hypothesised- (i) JAK/STAT signalling system regulates the Th17 cells in PsA and (ii) that tofacitinib which inhibits Jak-2 likely targets the Th17 cells by inhibiting the IL-23-induced JAK/STAT signalling system.
Mononuclear cells of peripheral blood (PBMC) and synovial fluid (SFMC) from patients with PsA (n=15) and PBMC from age/sex matched normal individuals (n=15) were collected. All patients had an active disease and were not on disease modifying anti-rheumatic drugs (DMARDS) or biologics. Recombinant IL-23 (rIL-23) (40 ng/mL) induced activated IL-17+ T cells were generated and evaluated as per our earlier reports.3 Cells were cultured with and without tofacitinib (50 nM). Western blot studies were performed to indentify Jak2/p-Jak2 and stat3/p-stat3 in the sorted activated CD3+ T cells. Hi-D fluorescence-activated cell sorting (FACS) studies were performed to identify the activated memory CD4+ CD11a+CD45RO+IL-17+ T cells and CD8+CD11a+CD45RO+IL-17+ T cells in SFMC/PBMC of PsA and PBMC of normal individuals.
In both PsA and controls sorted activated CD3+ T cells in the presence of IL-23 demonstrated activation of Jak2 and STAT3. Further, we noticed tofacitinib markedly inhibited phosphorylation of Jak2 and STAT-3, the signalling proteins induced by IL-23 (figure 1A–C).
Hi-D FACS analyses of the activated CD3+T cells in patients with PsA demonstrated that IL-23 induced marked upregulation of IL-17 in the memory T cells (CD11a+CD45RO+) (figure 2A). We noticed that SFMC and PBMC treated with rIL-23 in patients with PsA had 30±4.5% and 18±3.8% activated memory CD4+IL-17+ T cells, respectively, compared with 5±0.7% in healthy persons (p<0.001%). Further, we noticed that CD4+CD11a+CD45RO+IL-17+ T cells were 5±2% (p<0.001%) in cells treated with Tofacitinib (figure 2B). Tofacitinib also significantly inhibited proliferation of these CD4+CD11a+CD45RO+IL-17+ T cells (p<0.001%) (figure 2E).
Th17 cells play a critical role in the pathogenesis of PsA.3 ,4 Here, we observed that the generation of these pathological CD4+CD11a+CD45RO+IL-17+ T cells and their proliferation are regulated by the JAK-STAT signalling system. A plausible mechanism of action of tofacitinib likely to be inhibition of the IL-23/IL-17 cytokine axis by inhibiting the IL-23-induced JAK-STAT signalling system.
Contributors SKR: Reviewed and analysed data, helped to prepare the manuscript. CA: Performed experiments, analysed data and helped to prepare the manuscript. SPR: Designed the study, reviewed and analysed data, helped to prepare the manuscript.
Funding This project was supported by the VA Medical Center Sacramento.
Competing interests None declared.
Ethics approval IRB-VA Sacramento Medical Center.
Provenance and peer review Not commissioned; internally peer reviewed.
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