Background and purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Histone deacetylase inhibitors (HDACi), a new class of anti-cancer agents, have recently been reported to exhibit potent anti-inflammatory activities. A proof of concept study was carried out with suberoylanilide hydroxamic acid (SAHA) and MS-275, two HDACi currently undergoing clinical investigations for various oncological indications. Experimental approach: The anti-rheumatic effects of SAHA and MS-275 were assessed in both mouse and rat collagen induced arthritis (CIA) models. Key results: SAHA exhibited moderate prophylactic efficacy. It attenuated paw swelling due to inflammation, decreased bone erosion in both mice and rats and reduced slightly the RA-induced bone resorption in rats. However, SAHA could not inhibit the onset of arthritis. In contrast, MS-275 displayed dramatic anti-rheumatic activities. In prophylactic intervention, high doses of MS-275 prevented bone erosion and markedly delayed the onset of arthritis; at low doses, MS-275 strongly attenuated paw swelling, bone erosion, and bone resorption associated with RA. Furthermore, the therapeutic efficacy of MS-275 was also documented. After the onset of arthritis, it could stop the disease progression and joint destruction.. An anti inflammatory effect of MS-275 was also confirmed through its capacity to decrease serum IL-6 and IL-1b levels in the CIA induced mouse model. The anti-rheumatic activity of MS-275 was also confirmed through histological observation. No synovial hyperplasia, pannus formation, cartilage or bone destruction were observed in the high dose prophylactic intervention in mice. Conclusion and implication: This study strongly supported HDACi as an innovative therapeutic strategy for RA.
The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.
IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL-17C to AD pathogenesis, MOR106 was tested in two distinct in vivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our results indicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD.
Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).
Background Key pathogenic events of psoriasis and atopic eczema (AE) are misguided immune reactions of the skin. IL‐17C is an epithelial‐derived cytokine, whose impact on skin inflammation is unclear. Objective We sought to characterize the role of IL‐17C in human ISD. Methods IL‐17C gene and protein expression was assessed by immunohistochemistry and transcriptome analysis. Primary human keratinocytes were stimulated and expression of cytokines chemokines was determined by qRT‐PCR and luminex assay. Neutrophil migration towards supernatant of stimulated keratinocytes was assessed. IL‐17C was depleted using a new IL‐17C‐specific antibody (MOR106) in murine models of psoriasis (IL‐23 injection model) and AE (MC903 model) as well as in human skin biopsies of psoriasis and AE. Effects on cell influx (mouse models) and gene expression (human explant cultures) were determined. Results Expression of IL‐17C mRNA and protein was elevated in various ISD. We demonstrate that IL‐17C potentiates the expression of innate cytokines, antimicrobial peptides (IL‐36G, S100A7 and HBD2) and chemokines (CXCL8, CXCL10, CCL5 and VEGF) and the autocrine induction of IL‐17C in keratinocytes. Cell‐free supernatant of keratinocytes stimulated with IL‐17C was strongly chemotactic for neutrophils, thus demonstrating a critical role for IL‐17C in immune cell recruitment. IL‐17C depletion significantly reduced cell numbers of T cells, neutrophils and eosinophils in murine models of psoriasis and AE and led to a significant downregulation of inflammatory mediators in human skin biopsies of psoriasis and AE ex vivo. Conclusion IL‐17C amplifies epithelial inflammation in Th2 and Th17 dominated skin inflammation and represents a promising target for the treatment of ISD.
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