Childhood atopic dermatitis—Brain‐derived neurotrophic factor correlates with serum eosinophil cationic protein and disease severity

Several studies have shown that neurotrophins including brain‐derived neurotrophic factor (BDNF) play a role in chronic inflammatory skin diseases such as atopic dermatitis (AD). BDNF is increased in the serum samples of adults with AD. Interestingly, eosinophils of these patients can release and produce BDNF. We analyzed BDNF serum levels with ELISA and their correlation with SCORAD score, eosinophil cationic protein (ECP), total IgE, IL‐4, IL‐13 and IL‐31 in children with AD (n = 56) compared to nonatopic healthy children (n = 25). In addition, we analyzed FLG loss‐of‐function mutations in 17 children with AD and their connection to BDNF. BDNF serum levels were significantly higher in children with AD. Further, BDNF correlated with disease activity, serum ECP, and total IgE serum levels in AD. There was no difference in BDNF levels of filaggrin‐positive or filaggrin‐negative children with AD, and there was no correlation of BDNF with IL‐31 and Th2 cytokines including IL‐4 and IL‐13. Together, our data add new insights into the pathophysiology of AD, suggesting that serum BDNF which correlates with disease severity contributes to the regulation of inflammation in an eosinophil‐, but not Th2‐dependent manner.     

TSLP production by dendritic cells is modulated by IL‐1β and components of the endoplasmic reticulum stress response

Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of T_H2‐cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and β‐glucans requires dectin‐1, Syk, NF‐κB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL‐1β, but not TNF‐α, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol‐requiring transmembrane kinase/endonuclease 1 and protein kinase R‐like ER kinase, which are activated by dectin‐1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin‐1, the IL‐1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC‐controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue.     

Thymic stromal lymphopoietin expression is increased in the horny layer of patients with atopic dermatitis

Thymic stromal lymphopoietin (TSLP) is known for its capacity to induce CD11c⁺ myeloid dendritic cells to promote T helper type 2 (Th2)‐skewed inflammatory responses. Although increased expression of TSLP was reported in the lesional skin of limited numbers of patients with atopic dermatitis (AD), the relationships between the degree of TSLP expression in the skin and the severity of AD, epidermal barrier function and eruption type remain to be elucidated. The aim of this study was to examine the relationships between the degree of TSLP expression in the skin and the severity of AD, eruption type and epidermal barrier function using a non‐invasive method in a sizeable group of the patients. Stratum corneum tissue was obtained from AD patients by tape stripping, and the stratum corneum TSLP (scTSLP) expression level was evaluated using a TSLP‐specific antibody followed by image analysis. The correlations between the scTSLP intensity and the severity scoring of AD (SCORAD) index and epidermal barrier function, such as stratum corneum hydration and transepidermal water loss (TEWL), were analysed. The changes in the scTSLP level induced by the application of moisturizer were also examined. The scTSLP expression level was increased in AD patients compared with healthy subjects and was correlated with SCORAD, especially with the dry skin score, and stratum corneum hydration. Moisturizer application resulted in reduced scTSLP levels. The scTSLP level can be used as a biomarker of AD severity and particularly epidermal barrier status.     

TSLP or IL‐7 provide an IL‐7Rα signal that is critical for human B lymphopoiesis

Thymic stromal lymphopoietin (TSLP) and IL‐7 are cytokines that signal via the IL‐7 receptor alpha (IL‐7Rα) to exert both overlapping and unique functions during early stages of mouse B‐cell development. In human B lymphopoiesis, the requirement for IL‐7Rα signaling is controversial and the roles of IL‐7 and TSLP are less clear. Here, we evaluated human B‐cell production using novel in vitro and xenograft models of human B‐cell development that provide selective IL‐7 and human TSLP (hTSLP) stimulation. We show that in vitro human B‐cell production is almost completely blocked in the absence of IL‐7Rα stimulation, and that either TSLP or IL‐7 can provide a signal critical for the production and proliferation of human CD19⁺ PAX5⁺ pro‐B cells. Analysis of primary human bone marrow stromal cells shows that they express both IL‐7 and TSLP, providing an in vivo source of these cytokines. We further show that the in vivo production of human pro‐B cells under the influence of mouse IL‐7 in a xenograft scenario is reduced by anti‐IL‐7 neutralizing antibodies, and that this loss can be restored by hTSLP at physiological levels. These data establish the importance of IL‐7Rα mediated signals for normal human B‐cell production.     

Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod‐induced psoriasis‐like inflammation

Oncostatin M (OSM) has been reported to be overexpressed in psoriasis skin lesions and to exert proinflammatory effects in vitro on human keratinocytes. Here, we report the proinflammatory role of OSM in vivo in a mouse model of skin inflammation induced by intradermal injection of murine OSM‐encoding adenovirus (AdOSM) and compare with that induced by IL‐6 injection. Here, we show that OSM potently regulates the expression of genes involved in skin inflammation and epidermal differentiation in murine primary keratinocytes. In vivo, intradermal injection of AdOSM in mouse ears provoked robust skin inflammation with epidermal thickening and keratinocyte proliferation, while minimal effect was observed after AdIL‐6 injection. OSM overexpression in the skin increased the expression of the S100A8/9 antimicrobial peptides, CXCL3, CCL2, CCL5, CCL20, and Th1/Th2 cytokines, in correlation with neutrophil and macrophage infiltration. In contrast, OSM downregulated the expression of epidermal differentiation genes, such as cytokeratin‐10 or filaggrin. Collectively, these results support the proinflammatory role of OSM when it is overexpressed in the skin. However, OSM expression was not required in the murine model of psoriasis induced by topical application of imiquimod, as demonstrated by the inflammatory phenotype of OSM‐deficient mice or wild‐type mice treated with anti‐OSM antibodies.     

MicroRNA‐155 may be involved in the pathogenesis of atopic dermatitis by modulating the differentiation and function of T helper type 17 (Th17) cells

Our aims were to identify the differential expression of microRNA (miR)‐155, as well as to explore the possible regulatory effects of miR‐155 on the differentiation and function of T helper type 17 (Th17) cells in atopic dermatitis (AD). The Th17 cell percentage and expression levels of miR‐155, retinoic acid‐related orphan receptor (ROR)γt, interleukin (IL)‐17 and suppressor of cytokine signalling‐1 (SOCS1) in peripheral CD4⁺ T cells, plasma and skin specimens were detected and compared in AD patients and healthy subjects. A miR‐155 mimic and an inhibitor were transfected separately into AD CD4⁺ T cells to confirm the in‐vivo data. The Th17 cell percentage, miR‐155 expression, RORγt mRNA expression, IL‐17 mRNA expression and plasma concentration were increased significantly in AD patients compared with healthy subjects. Conversely, SOCS1 mRNA expression and plasma concentration were decreased significantly. Similar results were detected in cultured CD4⁺ T cells transfected with the miR‐155 mimic compared with a miR‐155 inhibitor or a negative control. Additionally, there was a sequential decrease in miR‐155 expression, as well as RORγt and IL‐17 mRNA expression, but an increase in SOCS1 mRNA expression, from AD lesional skin and perilesional skin to normal skin. Positive correlations were found between miR‐155 expression and AD severity, Th17 cell percentage, RORγt mRNA expression and IL‐17 mRNA expression and plasma concentration, while negative correlations were observed between miR‐155 expression and SOCS1 mRNA expression and plasma concentration in AD peripheral circulation and skin lesions. In conclusion, miR‐155 is over‐expressed and may be involved in AD pathogenesis by modulating the differentiation and function of Th17 cells.     

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

Atopic dermatitis (AD) is a chronic inflammatory disease controlled by the innate and adaptive immune system. To elucidate the impact of innate immune signaling in AD, we analyzed MyD88‐deficient mice in a murine model of AD‐like dermatitis by epicutaneous sensitization with ovalbumin (OVA). Global MyD88 deficiency led to reduced epidermal thickening and diminished accumulation of macrophages within the inflamed skin. In addition, we observed impaired emigration of Langerhans cells (LCs) out of the epidermis of MyD88‐deficient mice. These findings indicate that MyD88 deficiency affects various skin‐resident cell types in the AD model. Moreover, production of IFN‐g, IL‐17, and CCL17 was reduced in skin draining lymph node cells and OVA‐specific immunoglobulin levels were lower in MyD88‐deficient mice. We further investigated the role of MyD88 in keratinocytes, as keratinocytes contribute to AD pathology. Exclusive expression of MyD88 in epidermal keratinocytes partially restored LC emigration after AD induction and expression of CCL17 in skin draining lymph nodes (LNs), but did not promote epidermal thickening nor production of IL‐17. Altogether, these data demonstrate that MyD88 signaling in keratinocytes is able to restore LC migration in an otherwise MyD88‐deficient background, and significantly contributes to the development of AD‐like dermatitis.     

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

Both thymic stromal lymphopoietin (TSLP) and IL‐13 are essential cytokines for the development of allergic inflammation. However, a causal link between TSLP and IL‐13 has not yet been fully elucidated. This study aimed to investigate whether IL‐13 induces TSLP expression and whether the induction contributes to the development of allergic inflammation. We found that IL‐13 induced TSLP expression in mouse nasal tissue specimens in a Stat6‐dependent manner. In addition, intranasal challenge of mice with IL‐13 induced TSLP expression in the nasal epithelium. Importantly, intranasal IL‐13 challenge induced eosinophilia and goblet cell hyperplasia in the nasal mucosa in mice, which was inhibited by the blockade of TSLP activity with anti‐TSLP Ab. These findings suggest that TSLP is an important mediator of IL‐13‐driven allergic inflammation in the nasal mucosa. Taken together with the recent findings that IL‐13 is a critical downstream element for TSLP‐driven allergic inflammation, TSLP may function both upstream and downstream of IL‐13, thus providing an additional rationale as to why TSLP plays such a central role in the development of allergic inflammation.     

Mechanisms of chorioamnionitis‐associated preterm birth: interleukin‐1β inhibits progesterone receptor expression in decidual cells

In chorioamnionitis (CAM), a major cause of preterm birth (PTB), maternal–fetal inflammation of the decidua and amniochorion cause the release of cytokines that elicit cervical ripening, fetal membrane rupture and myometrial activation. We posit that this inflammatory milieu triggers PTB by inhibiting progesterone receptor (PR) expression and increasing decidual prostaglandin (PG) production. Immunohistochemical staining of decidua detected significantly lower PR levels in decidual cells (DCs) from CAM‐complicated PTB. Incubation of DCs with IL‐1β decreased PR expression and significantly increased PGE₂ and PGF_2α production and COX‐2 expression. The addition of PGF_2α to DC cultures also suppressed PR expression. However, the COX inhibitor, indomethacin, did not reverse IL‐1β suppression of PR expression in DC cultures. Although IL‐1β treatment activated the NF‐K B, ERK1/2 and p38 MAPK signalling cascades in DCs, inhibition of ERK1/2 MAPK signalling alone was sufficient to completely reverse the suppression of PR levels by IL‐1β. These findings suggest that CAM‐associated PTB is induced at least in part by IL‐1β‐mediated functional progesterone withdrawal. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Role of podoplanin in the high interleukin‐17A secretion resulting from interactions between activated lymphocytes and psoriatic skin‐derived mesenchymal cells

In the context of psoriasis, T helper type 17 (Th17) cells infiltrate the inflammatory site and interact with local mesenchymal cells, including skin fibroblasts. The aim of this work was to study the interactions of skin‐derived fibroblasts with peripheral blood mononuclear cells (PBMC) with a focus on the Th17 pathway and to identify a mechanism which leads to a high interleukin (IL)?17 secretion. A co‐culture system between PBMC and skin fibroblasts was developed. Healthy and patient PBMC were added to non‐lesional or lesional skin fibroblasts at a 5:1 ratio for 48 h in the presence or not of activation with phytohaemagglutinin (PHA). Monocytes were removed or not by adherence before the co‐culture. An anti‐podoplanin antibody was also used during the co‐culture. Cytokine production (IL‐8, IL‐6, IL‐1β and IL‐17) was measured by enzyme‐linked immunosorbent assay (ELISA) and cell staining (CD3, CD4, IL‐17 and podoplanin) by flow cytometry. Without T cell receptor (TCR) activation, IL‐8, IL‐6 and IL‐1β production increased in PBMC‐fibroblast co‐culture compared to PBMC alone. No additional effect was observed with TCR activation, with no difference in the Th17 cell percentage in activated‐PBMC alone or co‐cultured. Conversely, IL‐17 production was increased highly only in co‐cultures between control and patient activated‐PBMC and skin fibroblasts. Removal of monocytes decreased cytokine production, notably that of IL‐17. Addition of an anti‐podoplanin antibody decreased IL‐17 secretion by 60%. Interactions between resting PBMC and fibroblasts induce the IL‐8, IL‐6 and IL‐1β production. PBMC activation and cell interactions are critical for a high IL‐17 secretion. Podoplanin contributes largely to this massive IL‐17 secretion.     

Emerging role of interleukin‐31 and interleukin‐31 receptor in pruritus in atopic dermatitis

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (T_H2)‐deviated immune reactions. Interleukin‐31 (IL‐31), preferentially produced from T_H2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti‐IL‐31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL‐31 and its receptor with special references to atopic itch.     

Association of Disease Severity with IL‐1 levels in Methotrexate‐treated Psoriasis Patients

Interleukin‐1 plays a key role in inflammation and keratinocyte activation. It is an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target. The aim of this study is to evaluate the effect of Methotrexate (MTX) on IL‐1 α and IL‐1 β levels in both plasma and skin biopsy of patients with psoriasis and to investigate their association with clinical disease activity. Forty‐five control subjects and 58 patients with psoriasis were recruited for this study. The patients were treated with 7.5 mg of MTX per week for 12 weeks. Folic acid was given at 5 mg once daily except on the day of MTX for 12 weeks. Blood samples and lesional skin biopsy were taken. Disease severity was assessed by Psoriasis Area Severity Index (PASI) score. IL‐1 levels in plasma and skin biopsy were analysed using ELISA. PASI score declined significantly (P < 0.001) from day 0 to 12 weeks of MTX treatment. IL‐1 α level in plasma and skin biopsy was reduced at day 0 sample and elevated significantly (P < 0.001) after MTX treatment. IL‐1β level in plasma and skin biopsy was higher at day 0 sample and reduced significantly (P < 0.001) after MTX treatment. IL‐1α levels and PASI score showed inverse correlation score before and after treatment with MTX. Whereas IL‐1β levels showed positive correlation before and after treatment with MTX. Decreasing IL‐1β levels by MTXs in psoriasis may block the Th17 differentiation. This shows the therapeutic effect of MTX in controlling the immunopathogenesis of psoriasis.     

Serum levels of epithelial‐derived mediators and interleukin‐4/interleukin‐13 signaling after bronchial challenge with Dermatophagoides pteronyssinus in patients with allergic asthma

Allergens are the main trigger that enhances airway type 2 inflammation, and the epithelium is the first line of defense that reacts to its exposure. Therefore, epithelial‐derived mediators, such as interleukin (IL)‐25, IL‐33, thymic stromal lymphopoietin (TSLP) and ezrin, may play a role as alarmins in IL‐4/IL‐13 signaling in allergic asthma (AA). We investigated the serum levels of IL‐25, IL‐33, TSLP, ezrin, IL‐4 and IL‐13, after bronchial challenge with Dermatophagoides pteronyssinus in patients with AA. We examined 18 subjects: nine steroid‐free stable patients with AA sensitized to D. pteronyssinus and nine non‐atopic healthy subjects (HS). Bronchial allergen challenge was performed using inhaled D. pteronyssinus allergen. IL‐4, IL‐13, IL‐25, IL‐33, TSLP and ezrin levels in serum were measured by ELISA at two time points ‐ before and 24 hours after bronchial allergen challenge. The serum levels of IL‐25, TSLP and ezrin did not differ between AA and HS groups at baseline. However, after allergen exposure, significant increases in serum levels of IL‐25, TSLP and ezrin were observed only in patients with AA. The serum level of IL‐33 at baseline was significantly higher in the AA group compared with HS, but the allergen challenge did not provoke an increase of this cytokine in any group. IL‐4 and IL‐13 levels were significantly higher at baseline in the AA group compared with HS and, after allergen exposure, were significantly increased in the AA group, with no effect on HS. Thus, the epithelial‐derived mediators IL‐25, TSLP and ezrin, via IL4/IL13 signaling, enhance type 2 inflammation after bronchial challenge with D. pteronyssinus in AA.     

Vitexin alleviates interleukin‐1β‐induced inflammatory responses in chondrocytes from osteoarthritis patients: Involvement of HIF‐1α pathway

It has been reported that vitexin has anti‐inflammatory effects in osteoarthritis (OA) rats. However, the effects of vitexin on interleukins‐1β (IL‐1β)‐stimulated OA patient‐derived chondrocytes have not been reported. The purpose of this study was to investigate the anti‐inflammatory effects of vitexin on IL‐1β‐stimulated human osteoarthritis chondrocytes and to reveal the involvement of hypoxia‐inducible factor 1α (HIF‐1α) pathway. Enzyme‐linked immunosorbent assay, quantitative real‐time PCR and Western blotting assays were employed. ELISA results demonstrated that the proinflammatory cytokine levels of interleukins‐6 (IL‐6) and tumour necrosis factor α (TNF‐α) in the serum and synovial fluid and HIF‐1α level in the synovial fluid were significantly elevated in OA patients compared to normal healthy subjects. Moreover, the Western blotting results indicated that the protein expression of HIF‐1α was significantly higher in the cartilage tissues of OA patients. OA patient‐derived chondrocytes were stimulated by IL‐1β and treated with different concentration of vitexin for 24 hours. Vitexin showed no cytotoxicity and increased the survival of chondrocytes under IL‐1β stimulation. Vitexin suppressed IL‐1β‐induced production of NO and prostaglandin E2 (PGE₂) in chondrocytes culture. The treatment of vitexin significantly inhibited IL‐1β‐induced expressions of proinflammatory cytokine levels of IL‐6, TNF‐α, matrix metalloproteinase (MMP)‐1, MMP‐3 and MMP‐13. Furthermore, Western blotting results demonstrated that HIF‐1α is involved in vitexin's protective effects on IL‐1β‐stimulated injuries in OA patient‐derived chondrocytes. Our study demonstrates that vitexin alleviates IL‐1β‐induced inflammatory responses in chondrocytes from osteoarthritis patients, which may be attributed partly to the inhibition of HIF‐1α pathway.     

IL‐17 and IL‐22 mediate IL‐20 subfamily cytokine production in cultured keratinocytes via increased IL‐22 receptor expression

IL‐20 cytokine subfamily members, including IL‐19, IL‐20, and IL‐24, are highly expressed in psoriatic skin lesions. Here, we demonstrate that psoriasis mediators IL‐17 and IL‐22 synergistically induce the production of IL‐20 subfamily proteins in cultured human keratinocytes. Interestingly, expression of the IL‐22 receptor (IL‐22R) also increased in epidermal lesions versus normal skin. IL‐22R over‐expression using an adenoviral vector to mimic psoriatic conditions in cultured keratinocytes significantly enhanced IL‐17‐ and IL‐22‐induced production of IL‐20 subfamily cytokines. Furthermore, IL‐17 and IL‐22 coordinately enhanced MIP‐3α, IL‐8, and heparin‐binding EGF‐like growth factor (HB‐EGF) production, depending on the amount of IL‐22R expression. Additionally, because IL‐20 and IL‐24 share the IL‐22R with IL‐22, the function of IL‐20 and IL‐24 was also increased. IL‐20 and IL‐24 have effects similar to that of IL‐22; IL‐24 showed more potent expression than IL‐20. A combination of IL‐24 and IL‐17 increased the production of MIP‐3α, IL‐8, and HB‐EGF, as did a combination of IL‐22 and IL‐17. These data indicate that increased IL‐22R expression in epidermal keratinocytes contributes to the pathogenesis of psoriasis through enhancing the coordinated effects of IL‐22 and IL‐17, inducing the production of the IL‐20 subfamily, chemokines, and growth factors.     

Complement C5a potentiates uric acid crystal‐induced IL‐1β production

Anaphylatoxin C5a released upon complement activation is associated with both acute and chronic inflammations such as gout. The pathogenesis of gout was identified as uric acid crystal deposition in the joints that activates inflammasome, leading to IL‐1β release. However, little is known about the interaction between complement activation and monosodium urate/uric acid (MSU) crystal‐induced inflammasome activation or IL‐1β production. Here, we report that MSU crystal‐induced proinflammatory cytokines/chemokines in human whole blood is predominantly regulated by C5a through its interaction with C5a receptor. C5a induces pro‐IL‐1β and IL‐1β production in human primary monocytes, and potentiates MSU or cholesterol crystals in IL‐1β production. This potentiation is caspase‐1 dependent and requires intracellular Ca²⁺ mobilization, K⁺ efflux, and cathepsin B activity. Our results provide insight into the role of C5a as an endogenous priming signal that is required for the initiation of uric acid crystal‐induced IL‐1β production. C5a could potentially be a therapeutic target together with IL‐1β antagonists for the treatment of complement‐dependent and inflammasome‐associated diseases.     

Distinct expression of interleukin (IL)‐36α, β and γ, their antagonist IL‐36Ra and IL‐38 in psoriasis,rheumatoid arthritis and Crohn's disease

Interleukin (IL)‐36α, IL‐36β and IL‐36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL‐36Ra or IL‐38, another potential IL‐36 inhibitor, limit uncontrolled inflammation. The expression and role of IL‐36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod‐induced mouse skin inflammation and in human psoriasis, expression of IL‐36α, γ and IL‐36Ra, but not IL‐36β and IL‐38 mRNA, was induced and correlated with IL‐1β and T helper type 17 (Th17) cytokines (IL‐17A, IL‐22, IL‐23, CCL20). In mice with collagen‐induced arthritis and in the synovium of patients with RA, IL‐36α, β, γ, IL‐36Ra and IL‐38 were all elevated and correlated with IL‐1β, CCL3, CCL4 and macrophage colony‐stimulating factor (M‐CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium‐induced colitis and in patients with CD, only IL‐36α, γ and IL‐38 were induced at relatively low levels and correlated with IL‐1β and IL‐17A. We suggest that only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL‐36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL‐36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL‐36β and IL‐36Ra were produced constitutively, but IL‐36α, γ and IL‐38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL‐36 agonists/antagonists ratio.     

IL‐1β/HMGB1 Complexes Promote The PGE2 Biosynthesis Pathway in Synovial Fibroblasts

PGE₂ is a potent lipid mediator of pain and oedema found elevated in RA. Microsomal prostaglandin E synthase‐1 (mPGES‐1) is a terminal enzyme of the PGE₂ pathway inducible by proinflammatory cytokines. mPGES‐1 is markedly upregulated in RA synovial tissue despite antirheumatic treatments, suggesting that multiple inflammatory stimuli contribute to its induction. High‐mobility group box chromosomal protein 1 (HMGB1) is known to induce inflammation both by direct interaction with TLR4 and by enhancement of other proinflammatory molecules signalling, through complex formation. The high expression of extracellular HMGB1 within the inflamed synovium, implies its pro‐arthritogenic role in RA. We aimed to investigate the effects of IL‐1β/HMGB1 complexes on mPGES‐1 and other enzymes of the PGE₂ pathway in synovial fibroblasts (SFs) from patients with arthritis. Furthermore, we studied the effect of COX‐2 inhibition and IL‐1RI antagonism on prostanoid and cytokine production by SFs. Stimulation of SFs with HMGB1 in complex with suboptimal amounts of IL‐1β significantly increased mPGES‐1 and COX‐2 expressions as well as PGE₂ production, as compared to treatment with HMGB1 or IL‐1β alone. Furthermore, NS‐398 reduced the production of IL‐6 and IL‐8, thus indicating that IL‐1β/HMGB1 complexes modulate cytokine production in part through prostanoid synthesis. Treatment with IL‐1RA completely abolished the induced PGE₂ and cytokine production, suggesting an effect mediated through IL‐1RI. IL‐1β/HMGB1 complexes promote the induction of mPGES‐1, COX‐2 and PGE₂ in SF. The amplification of the PGE₂ biosynthesis pathway by HMGB1 might constitute an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis.