YKL-40 as a Novel Factor Associated with Inflammation and Catabolic Mechanisms in Osteoarthritic Joints

YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients (r=0.37, P=0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 (r=0.36, P=0.014), MMP-3 (r=0.46, P=0.001), IL-6 (r=0.57, P<0.001), and IL-17 (r=0.52, P=0.010) levels. Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA

YKL-40 as a novel factor associated with inflammation and catabolic mechanisms in osteoarthritic joints,”

YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients ( = 0.37, = 0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 ( = 0.36, = 0.014), MMP-3 ( = 0.46, = 0.001), IL-6 ( = 0.57, &lt; 0.001), and IL-17 ( = 0.52, = 0.010) levels. Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA

YKL-40 as a novel factor associated with inflammation and catabolic mechanisms in osteoarthritic joints

YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients ( = 0.37, = 0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 ( = 0.36, = 0.014), MMP-3 ( = 0.46, = 0.001), IL-6 ( = 0.57, < 0.001), and IL-17 ( = 0.52, = 0.010) levels.Moreover, IL-6 and IL-17 enhanced YKL-40 production in human primary chondrocyte cultures. The present study introduces YKL-40 as a cartilage-derived factor associated with mediators of inflammation and cartilage destruction involved in the pathogenesis of OA.Copyright © 2014 Tuija Väänänen et al. This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Transient receptor potential ankyrin 1 (TRPA1) is functionally expressed in primary human osteoarthritic chondrocytes

Transient receptor potential ankyrin 1 (TRPA1) is a membrane-associated cation channel, widely expressed in neuronal cells and involved in nociception and neurogenic inflammation. We showed recently that TRPA1 mediates cartilage degradation and joint pain in the MIA-model of osteoarthritis (OA) suggesting a hitherto unknown role for TRPA1 in OA. Therefore, we aimed to investigate whether TRPA1 is expressed and functional in human OA chondrocytes. METHODS: Expression of TRPA1 in primary human OA chondrocytes was assessed by qRT-PCR and Western blot. The functionality of the TRPA1 channel was assessed by Ca(2+)-influx measurements. Production of MMP-1, MMP-3, MMP-13, IL-6, and PGE2 subsequent to TRPA1 activation was measured by immunoassay. RESULTS: We show here for the first time that TRPA1 is expressed in primary human OA chondrocytes and its expression is increased following stimulation with inflammatory factors IL-1β, IL-17, LPS, and resistin. Further, the TRPA1 channel was found to be functional, as stimulation with the TRPA1 agonist AITC caused an increase in Ca(2+) influx, which was attenuated by the TRPA1 antagonist HC-030031. Genetic depletion and pharmacological inhibition of TRPA1 downregulated the production of MMP-1, MMP-3, MMP-13, IL-6, and PGE2 in osteoarthritic chondrocytes and murine cartilage, respectively. CONCLUSIONS: The TRPA1 cation channel was found to be functionally expressed in primary human OA chondrocytes, which is an original finding. The presence and inflammatory and catabolic effects of TRPA1 in human OA chondrocytes propose a highly intriguing role for TRPA1 as a pathogenic factor and drug target in OA.BioMed Central open access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

We report the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19. Of the 208 patients recruited from 11 Finnish hospitals, 198 survived, of whom 181 (92%) completed follow-up. At one year, self-reported recovery occurred in 85% in remdesivir and 86% in standard of care (SoC) (RR 0.94, 95% CI 0.47-1.90). We infer no convincing difference between remdesivir and SoC in quality of life or symptom outcomes (p > 0.05). Of the 21 potential long-COVID symptoms, patients reported moderate/major bother from fatigue (26%), joint pain (22%), and problems with memory (19%) and attention/concentration (18%). In conclusion, after a one-year follow-up of hospitalized patients, one in six reported they had not recovered well from COVID-19. Our results provide no convincing evidence of remdesivir benefit, but wide confidence intervals included possible benefit and harm.publishedVersionPeer reviewe

Remdesiviiri sairaalahoitoisessa COVID-19-taudissa : pragmaattinen, adaptiivinen, satunnaistettu Solidarity Finland -monikeskustutkimus

Lähtökohdat : Remdesiviiriä tutkittiin Solidarity Finland -tutkimuksessa. Menetelmät : COVID-19-taudin takia sairaalahoitoon joutuneet potilaat satunnaistettiin saamaan standardihoitoa tai sen lisäksi remdesiviiriä. Solidarity-tutkimuksessa ja satunnaistettujen ­tutkimusten meta-analyysissä ensisijainen päätetapahtuma oli sairaalahoitoajan kuolleisuus. Tulokset : Rekrytoimme 208 potilasta yhdestätoista sairaalasta. Sairaalahoidon aikana ­remdesiviiriryhmässä (n = 114) kuoli 1 % ja standardihoitoryhmässä (n = 94) 4 %. Invasiiviseen hengityslaitehoitoon joutui 5 % molemmissa ryhmissä. Tehohoitoa sai 11 % remdesiviiri- ja 12 % standardihoitoryhmässä. Maksaentsyymit nousivat merkittävästi 5 %:lla remdesiviiri- ja 2 %:lla standardihoitoryhmässä. Meta-analyysin alaryhmäanalyysissä remdesiviiri vähensi kuoleman riskiä potilailla, jotka eivät sairaalahoidon alkaessa saaneet hengityslaitehoitoa (RR 0,85, 95 % LV 0,75­–0,96). Päätelmät : Suomessa on pandemian aikana mahdollista rekrytoida merkittävä määrä potilaita suuriin, satunnaistettuihin tutkimuksiin, joilla voidaan saada luotettavia tuloksia nopeasti. Remdesiviiristä voi olla apua sairaalahoitoisessa COVID-19-taudissa varhain aloitettuna.publishedVersionPeer reviewe

Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

We report the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19. Of the 208 patients recruited from 11 Finnish hospitals, 198 survived, of whom 181 (92%) completed follow-up. At one year, self-reported recovery occurred in 85% in remdesivir and 86% in standard of care (SoC) (RR 0.94, 95% CI 0.47-1.90). We infer no convincing difference between remdesivir and SoC in quality of life or symptom outcomes (p > 0.05). Of the 21 potential long-COVID symptoms, patients reported moderate/major bother from fatigue (26%), joint pain (22%), and problems with memory (19%) and attention/concentration (18%). In conclusion, after a one-year follow-up of hospitalized patients, one in six reported they had not recovered well from COVID-19. Our results provide no convincing evidence of remdesivir benefit, but wide confidence intervals included possible benefit and harm.Peer reviewe

PPAR-agonistien vaikutukset makrofagien aktivaatioon

PPAR-agonistien vaikutukset makrofagien aktivaatioon Tulehdus on keskeinen tekijä sekä perinteisten tulehdussairauksien, kuten nivelreuman, että lihavuuteen liittyvien sairauksien, kuten aikuistyypin diabeteksen ja sydän- ja verisuonisairauksien, tautiprosesseissa. Nivelreumassa liiallinen tulehdusreaktio aiheuttaa kudostuhoa ja kipua sekä hankaloittaa potilaan kykyä työskennellä ja toimia yhteiskunnassa. Lihavuuteen liittyvä tulehdus on voimakkuudeltaan hiljaisempaa kuin nivelreumassa, mutta silti tulehdus heikentää kudosten ja elinten toimintaa. Peroksisomin proliferaattoriaktivoidut reseptorit (PPAR:t) ovat solun sisäisiä proteiineja, jotka elimistön rasvahappomolekyylien pitoisuuden noustessa käynnistävät solussa rasvahappojen pilkkomiseen tarvittavien proteiinien valmistamisen. PPAR:ien aktiivisuutta lisääviä lääkkeitä tiatsolidiinidioneja ja fibraatteja käytetään aikuistyypin diabeteksen ja sydän- ja verisuonisairauksille altistavan korkean veren kolesterolipitoisuuden hoidossa. Viime aikoina PPAR:ien on havaittu osallistuvan solujen energia-aineenvaihdunnan lisäksi myös tulehdusreaktion säätelyyn. Tässä väitöskirjatyössä tutkittiin PPAR:ien aktiivisuutta lisäävien lääkkeiden, PPAR-agonistien, vaikutusta eräiden valkosoluihin kuuluvien syöjäsolujen, makrofagien, aktiivisuuteen. Väitöskirjatyössä havaittiin, että PPARα- ja PPARγ-agonistit vähensivät makrofagien tulehdusaktiivisuutta sekä soluviljelyssä että hiiren tulehdusmallissa. Tämä tulehdusta hillitsevä vaikutus antaa syyn olettaa, että PPAR-agonistit voisivat olla hyödyllisiä lääkkeitä aineenvaihduntasairauksien lisäksi pitkäaikaisissa tulehdussairauksissa kuten nivelreumassa. PPARα-agonistit myös vähensivät makrofagien kudosvaurion paranemista tukevaa aktiivisuutta, mikä on toivottava ominaisuus erityisesti sairauksissa, joihin liittyy liiallinen sidekudoksen muodostuminen. Tällaisia sairauksia ovat monet reumatauteihin kuuluvat sidekudossairaudet, kuten systeeminen skleroosi. Jotta PPAR-agonistien vaikutukset sekä solujen aineenvaihduntaan että tulehdukseen saataisiin parhaiten hyödynnettyä ilman sivuvaikutuksia, olisi optimaalista, että lääkeaine voitaisiin annostella paikallisesti haluttuun kohteeseen. Väitöskirjatyön yhteydessä valmistettiinkin sekä PPARα:aa että PPARγ:aa aktivoivaa muraglitatsaaria vapauttava biohajoava verisuonistentti. Väitöskirjatutkimuksessa näytetyt soluviljelytason tulokset osoittavat, että lääkeaineen vapautuminen stentistä tapahtuu sopivalla nopeudella ja että stentti hillitsee tulehdusta toivotulla tavalla. Tulehduksen ja aineenvaihdunnan yhteys on havainto, joka voi tulla mullistamaan paitsi lihavuuteen liittyvien sairauksien myös kroonisten tulehdussairauksien lääkehoidon. Tämä tutkimus vahvistaa hypoteesia PPAR:sta välittäjänä aineenvaihdunnan ja tulehduksen välillä. PPAR:t ovat lupaavia uusien reuman hoidossa käytettävien lääkkeiden vaikutuskohteita.Inflammation plays a central role in the pathophysiology of several chronic diseases. Although the role of inflammation in traditional inflammatory diseases, like in rheumatoid diseases, is better understood, it is believed that inflammation is also involved in other chronic conditions, for example in several metabolic diseases. In rheumatoid diseases, the overwhelming inflammation causes tissue damage, joint erosion and subsequent pain or abnormal tissue healing with fibrosis, both of which often lead to disability and represent a serious burden both to the individual patient and to society. Although a wide range of immunomodulating therapeutics are available, a significant number of patients with rheumatoid diseases do not obtain even adequate relief with the current treatments. The concept of the interaction between metabolism and inflammation has revealed new avenues in inflammation research. In metabolic diseases, the intensity of inflammation is lower than in traditional inflammatory diseases, but over time, it insidiously impairs the function of tissues and organs. Although the close relationship between metabolism and inflammation is now becoming clear, very little is known about the mechanisms that are underlying this interaction. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that were originally found to regulate glucose and fatty acid metabolism in cells. The PPARα agonists, fibrates, are old lipid-lowering drugs that are currently used in the treatment of hypertriglyceridemia. The PPARγ agonists, thiazolidinediones, are a group of insulin sensitizing drugs that became available for the treatment of type II diabetes mellitus in the late 1990s. Interestingly, PPARs have later been found to affect inflammatory responses. The aim of the present study was to investigate the immunomodulating properties of PPAR agonists with the focus on macrophage activation. Both PPARα and PPARγ agonists suppressed lipopolysaccharide (LPS)-induced classical activation of macrophages as shown by reduced production of proinflammatory mediators interleukin 6 (IL-6) and nitric oxide and protein levels of the inducible nitric oxide synthase (iNOS) by PPAR agonists in J774 murine macrophages. The effects of PPAR agonists on iNOS expression were studied in more detail and PPARα and PPARγ agonists were found to suppress iNOS expression via different mechanisms. PPARγ agonists reduced the transcription of iNOS, whereas PPARα agonists had no effect on iNOS transcription. Instead, PPARα agonists increased the degradation of iNOS protein through the proteasome pathway. PPARα and PPARγ agonists also had different effects on IL-4 + IL-13 –induced alternative activation of J774 macrophages, a phenomenon linked to fibrotic diseases, for example. PPARγ agonists increased the levels of three alternative activation markers, arginase 1, found in inflammatory zone 1 (fizz1) and mannose receptor 1. In contrast, PPARα agonists decreased the levels of these markers. Similarly to murine J774 cells, PPARα agonists also reduced the levels of alternative activation markers in human THP-1 monocyte-macrophages. This is the first study where the anti-inflammatory properties of a dual PPARα/γ agonist muraglitazar were characterized. Similarly to both PPARα and PPARγ agonists, muraglitazar suppressed the production of IL-6 and nitric oxide and the expression of iNOS in classically activated macrophages. Muraglitazar also attenuated the development of carrageenan-induced paw oedema in mice. In parallel to the results in vitro, IL-6, iNOS and tumour necrosis factor (TNF) mRNA levels were also lower in carrageenan-induced paw inflammation in muraglitazar-treated than in control mice in vivo. Finally, as an example of novel applications that would combine the benefits of muraglitazar in both metabolism and inflammatory pathways, a muraglitazar-eluting degradable vascular stent was manufactured. In the experiments reported in this study, the biological efficacy of muraglitazar was retained during the manufacturing process of the drug-coated stent. The drug-elution kinetics of the muraglitazar-coated stent was also promising thus representing a promising basis for further studies. Although the current anti-inflammatory therapeutic agents have significantly improved the prognosis of the patients with rheumatoid diseases, novel pharmacological approaches are needed to treat those patients who do not appropriately respond to the medications or are not able, for some reason, to use the drugs. The link between inflammation and metabolism may offer a new option to treat the traditional inflammatory diseases. This study supports the hypothesis of PPARs as important players or channels between metabolism and inflammation. PPARs are promising targets in the development of new antirheumatic pharmaceutics

PPAR-agonistien vaikutukset makrofagien aktivaatioon

PPAR-agonistien vaikutukset makrofagien aktivaatioon Tulehdus on keskeinen tekijä sekä perinteisten tulehdussairauksien, kuten nivelreuman, että lihavuuteen liittyvien sairauksien, kuten aikuistyypin diabeteksen ja sydän- ja verisuonisairauksien, tautiprosesseissa. Nivelreumassa liiallinen tulehdusreaktio aiheuttaa kudostuhoa ja kipua sekä hankaloittaa potilaan kykyä työskennellä ja toimia yhteiskunnassa. Lihavuuteen liittyvä tulehdus on voimakkuudeltaan hiljaisempaa kuin nivelreumassa, mutta silti tulehdus heikentää kudosten ja elinten toimintaa. Peroksisomin proliferaattoriaktivoidut reseptorit (PPAR:t) ovat solun sisäisiä proteiineja, jotka elimistön rasvahappomolekyylien pitoisuuden noustessa käynnistävät solussa rasvahappojen pilkkomiseen tarvittavien proteiinien valmistamisen. PPAR:ien aktiivisuutta lisääviä lääkkeitä tiatsolidiinidioneja ja fibraatteja käytetään aikuistyypin diabeteksen ja sydän- ja verisuonisairauksille altistavan korkean veren kolesterolipitoisuuden hoidossa. Viime aikoina PPAR:ien on havaittu osallistuvan solujen energia-aineenvaihdunnan lisäksi myös tulehdusreaktion säätelyyn. Tässä väitöskirjatyössä tutkittiin PPAR:ien aktiivisuutta lisäävien lääkkeiden, PPAR-agonistien, vaikutusta eräiden valkosoluihin kuuluvien syöjäsolujen, makrofagien, aktiivisuuteen. Väitöskirjatyössä havaittiin, että PPARα- ja PPARγ-agonistit vähensivät makrofagien tulehdusaktiivisuutta sekä soluviljelyssä että hiiren tulehdusmallissa. Tämä tulehdusta hillitsevä vaikutus antaa syyn olettaa, että PPAR-agonistit voisivat olla hyödyllisiä lääkkeitä aineenvaihduntasairauksien lisäksi pitkäaikaisissa tulehdussairauksissa kuten nivelreumassa. PPARα-agonistit myös vähensivät makrofagien kudosvaurion paranemista tukevaa aktiivisuutta, mikä on toivottava ominaisuus erityisesti sairauksissa, joihin liittyy liiallinen sidekudoksen muodostuminen. Tällaisia sairauksia ovat monet reumatauteihin kuuluvat sidekudossairaudet, kuten systeeminen skleroosi. Jotta PPAR-agonistien vaikutukset sekä solujen aineenvaihduntaan että tulehdukseen saataisiin parhaiten hyödynnettyä ilman sivuvaikutuksia, olisi optimaalista, että lääkeaine voitaisiin annostella paikallisesti haluttuun kohteeseen. Väitöskirjatyön yhteydessä valmistettiinkin sekä PPARα:aa että PPARγ:aa aktivoivaa muraglitatsaaria vapauttava biohajoava verisuonistentti. Väitöskirjatutkimuksessa näytetyt soluviljelytason tulokset osoittavat, että lääkeaineen vapautuminen stentistä tapahtuu sopivalla nopeudella ja että stentti hillitsee tulehdusta toivotulla tavalla. Tulehduksen ja aineenvaihdunnan yhteys on havainto, joka voi tulla mullistamaan paitsi lihavuuteen liittyvien sairauksien myös kroonisten tulehdussairauksien lääkehoidon. Tämä tutkimus vahvistaa hypoteesia PPAR:sta välittäjänä aineenvaihdunnan ja tulehduksen välillä. PPAR:t ovat lupaavia uusien reuman hoidossa käytettävien lääkkeiden vaikutuskohteita.Inflammation plays a central role in the pathophysiology of several chronic diseases. Although the role of inflammation in traditional inflammatory diseases, like in rheumatoid diseases, is better understood, it is believed that inflammation is also involved in other chronic conditions, for example in several metabolic diseases. In rheumatoid diseases, the overwhelming inflammation causes tissue damage, joint erosion and subsequent pain or abnormal tissue healing with fibrosis, both of which often lead to disability and represent a serious burden both to the individual patient and to society. Although a wide range of immunomodulating therapeutics are available, a significant number of patients with rheumatoid diseases do not obtain even adequate relief with the current treatments. The concept of the interaction between metabolism and inflammation has revealed new avenues in inflammation research. In metabolic diseases, the intensity of inflammation is lower than in traditional inflammatory diseases, but over time, it insidiously impairs the function of tissues and organs. Although the close relationship between metabolism and inflammation is now becoming clear, very little is known about the mechanisms that are underlying this interaction. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that were originally found to regulate glucose and fatty acid metabolism in cells. The PPARα agonists, fibrates, are old lipid-lowering drugs that are currently used in the treatment of hypertriglyceridemia. The PPARγ agonists, thiazolidinediones, are a group of insulin sensitizing drugs that became available for the treatment of type II diabetes mellitus in the late 1990s. Interestingly, PPARs have later been found to affect inflammatory responses. The aim of the present study was to investigate the immunomodulating properties of PPAR agonists with the focus on macrophage activation. Both PPARα and PPARγ agonists suppressed lipopolysaccharide (LPS)-induced classical activation of macrophages as shown by reduced production of proinflammatory mediators interleukin 6 (IL-6) and nitric oxide and protein levels of the inducible nitric oxide synthase (iNOS) by PPAR agonists in J774 murine macrophages. The effects of PPAR agonists on iNOS expression were studied in more detail and PPARα and PPARγ agonists were found to suppress iNOS expression via different mechanisms. PPARγ agonists reduced the transcription of iNOS, whereas PPARα agonists had no effect on iNOS transcription. Instead, PPARα agonists increased the degradation of iNOS protein through the proteasome pathway. PPARα and PPARγ agonists also had different effects on IL-4 + IL-13 –induced alternative activation of J774 macrophages, a phenomenon linked to fibrotic diseases, for example. PPARγ agonists increased the levels of three alternative activation markers, arginase 1, found in inflammatory zone 1 (fizz1) and mannose receptor 1. In contrast, PPARα agonists decreased the levels of these markers. Similarly to murine J774 cells, PPARα agonists also reduced the levels of alternative activation markers in human THP-1 monocyte-macrophages. This is the first study where the anti-inflammatory properties of a dual PPARα/γ agonist muraglitazar were characterized. Similarly to both PPARα and PPARγ agonists, muraglitazar suppressed the production of IL-6 and nitric oxide and the expression of iNOS in classically activated macrophages. Muraglitazar also attenuated the development of carrageenan-induced paw oedema in mice. In parallel to the results in vitro, IL-6, iNOS and tumour necrosis factor (TNF) mRNA levels were also lower in carrageenan-induced paw inflammation in muraglitazar-treated than in control mice in vivo. Finally, as an example of novel applications that would combine the benefits of muraglitazar in both metabolism and inflammatory pathways, a muraglitazar-eluting degradable vascular stent was manufactured. In the experiments reported in this study, the biological efficacy of muraglitazar was retained during the manufacturing process of the drug-coated stent. The drug-elution kinetics of the muraglitazar-coated stent was also promising thus representing a promising basis for further studies. Although the current anti-inflammatory therapeutic agents have significantly improved the prognosis of the patients with rheumatoid diseases, novel pharmacological approaches are needed to treat those patients who do not appropriately respond to the medications or are not able, for some reason, to use the drugs. The link between inflammation and metabolism may offer a new option to treat the traditional inflammatory diseases. This study supports the hypothesis of PPARs as important players or channels between metabolism and inflammation. PPARs are promising targets in the development of new antirheumatic pharmaceutics

Peroxisome proliferator-activated receptor alpha and gamma agonists differently regulate classical and alternative macrophage activation

Peroxisome proliferator-activated receptor (PPAR) agonists, fibrates and thiazolidinediones, are commonly used drugs in the treatment of dyslipidemia and diabetes. Their targets, PPARα and PPARγ, have also been shown to have a role in the regulation of inflammatory responses linking metabolism and inflammation. In the present study we investigated the effects of PPAR agonists on macrophage activation. In addition to the proinflammatory classical activation, we also focused on interleukin (IL) 4 and 13 -induced alternative activation which is a significant macrophage phenotype in tissue repairing processes and in fibrosing diseases. PPARα agonists GW7647 and fenofibrate as well as PPARγ agonist GW1929 inhibited lipopolysaccharide-induced classical macrophage activation and production of the characteristic biomarkers of this phenotype, i.e. IL-6 and nitric oxide, in murine J774 macrophages. Remarkably, the PPARα agonists also inhibited IL-4 and IL-13 –induced expression of alternative activation markers arginase-1, fizz1 and mannose receptor 1 whereas the PPARγ agonist GW1929 enhanced their expression in J774 macrophages. The PPARα agonists GW7647 and fenofibrate also attenuated the production of alternative activation markers chemokine (C-C motif) ligand 13 and plateletderived growth factor in human THP-1 macrophages. The present findings show that PPARα and PPARγ agonists differently regulate classical and alternative macrophage phenotypes. Furthermore, PPARα activation was introduced as a novel concept to down-regulate alternative macrophage activation indicating that PPARα agonists have therapeutic potential in conditions associated with aberrant alternative macrophage activation such as fibrosing diseases