TY - GEN A1 - Plöhn, Svenja A1 - Edelmann, Bärbel A1 - Japtok, Lukasz A1 - He, Xingxuan A1 - Hose, Matthias A1 - Hansen, Wiebke A1 - Schuchman, Edward H. A1 - Eckstein, Anja A1 - Berchner-Pfannschmidt, Utta T1 - CD40 enhances sphingolipids in orbital fibroblasts BT - potential role of sphingosine-1-phosphate in inflammatory T-cell migration in Graves' orbitopathy T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - PURPOSE. Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1099 KW - Grave’s orbitopathy KW - sphingosine-1-phosphate KW - sphingolipids KW - inflammation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468837 SN - 1866-8372 IS - 1099 ER - TY - JOUR A1 - Plöhn, Svenja A1 - Edelmann, Bärbel A1 - Japtok, Lukasz A1 - He, Xingxuan A1 - Hose, Matthias A1 - Hansen, Wiebke A1 - Schuchman, Edward H. A1 - Eckstein, Anja A1 - Berchner-Pfannschmidt, Utta T1 - CD40 enhances sphingolipids in orbital fibroblasts BT - potential role of sphingosine-1-phosphate in inflammatory T-Cell migration in graves' orbitopathy JF - Investigative ophthalmology & visual science N2 - METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. KW - inflammation Y1 - 2018 U6 - https://doi.org/10.1167/iovs.18-25466 SN - 0146-0404 SN - 1552-5783 VL - 59 IS - 13 SP - 5391 EP - 5397 PB - Association for Research in Vision and Opthalmology CY - Rockville ER - TY - GEN A1 - Krupkova, Olga A1 - Sadowska, Aleksandra A1 - Kameda, Takuya A1 - Hitzl, Wolfgang A1 - Hausmann, Oliver Nic A1 - Klasen, Jürgen A1 - Wuertz-Kozak, Karin T1 - p38 MaPK facilitates crosstalk between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc T2 - Postprints der Universität Potsdam : Humanwissenschaftliche Reihe N2 - Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1 beta, and TNF-alpha was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1 beta and TNF-alpha. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 mu M) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-alpha (5 and 10 ng/mL) did not activate ER stress, while IL-1 beta (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+](i) flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 705 KW - intervertebral disc KW - inflammation KW - endoplasmic reticulum stress KW - p38 MAPK KW - CHOP KW - GADD153 KW - GRP78 KW - IL-6 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468698 SN - 1866-8364 IS - 705 ER - TY - JOUR A1 - Krupkova, Olga A1 - Sadowska, Aleksandra A1 - Kameda, Takuya A1 - Hitzl, Wolfgang A1 - Hausmann, Oliver Nic A1 - Klasen, Jürgen A1 - Wuertz-Kozak, Karin T1 - p38 MaPK Facilitates crosstalk Between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc JF - Frontiers in Immunology N2 - Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1 beta, and TNF-alpha was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1 beta and TNF-alpha. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 mu M) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-alpha (5 and 10 ng/mL) did not activate ER stress, while IL-1 beta (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+](i) flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD. KW - intervertebral disc KW - inflammation KW - endoplasmic reticulum stress KW - p38 MAPK KW - CHOP KW - GADD153 KW - GRP78 KW - IL-6 Y1 - 2018 U6 - https://doi.org/10.3389/fimmu.2018.01706 SN - 1664-3224 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol JF - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - https://doi.org/10.3390/nu10091326 SN - 2072-6643 VL - 10 IS - 9 SP - 1 EP - 17 PB - Molecular Diversity Preservation International (MDPI) CY - Basel ER - TY - GEN A1 - Henkel, Janin A1 - Alfine, Eugenia A1 - Saín, Juliana A1 - Jöhrens, Korinna A1 - Weber, Daniela A1 - Castro, José Pedro A1 - König, Jeannette A1 - Stuhlmann, Christin A1 - Vahrenbrink, Madita A1 - Jonas, Wenke A1 - Kleinridders, André A1 - Püschel, Gerhard Paul T1 - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol T2 - Nutrients N2 - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 479 KW - non-alcoholic fatty liver disease (NAFLD) KW - NASH KW - cholesterol KW - PUFA KW - inflammation KW - oxidative stress Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-419773 ER - TY - JOUR A1 - Krupkova, Olga A1 - Smolders, Lucas A1 - Würtz-Kozak, Karin A1 - Cook, James A1 - Pozzi, Antonio T1 - The pathobiology of the meniscus BT - a comparison between the human and dog JF - Frontiers in veterinary science N2 - Serious knee pain and related disability have an annual prevalence of approximately 25% on those over the age of 55 years. As curative treatments for the common knee problems are not available to date, knee pathologies typically progress and often lead to osteoarthritis (OA). While the roles that the meniscus plays in knee biomechanics are well characterized, biological mechanisms underlying meniscus pathophysiology and roles in knee pain and OA progression are not fully clear. Experimental treatments for knee disorders that are successful in animal models often produce unsatisfactory results in humans due to species differences or the inability to fully replicate disease progression in experimental animals. The use of animals with spontaneous knee pathologies, such as dogs, can significantly help addressing this issue. As microscopic and macroscopic anatomy of the canine and human menisci are similar, spontaneous meniscal pathologies in canine patients are thought to be highly relevant for translational medicine. However, it is not clear whether the biomolecular mechanisms of pain, degradation of extracellular matrix, and inflammatory responses are species dependent. The aims of this review are (1) to provide an overview of the anatomy, physiology, and pathology of the human and canine meniscus, (2) to compare the known signaling pathways involved in spontaneous meniscus pathology between both species, and (3) to assess the relevance of dogs with spontaneous meniscal pathology as a translational model. Understanding these mechanisms in human and canine meniscus can help to advance diagnostic and therapeutic strategies for painful knee disorders and improve clinical decision making. KW - meniscus KW - inflammation KW - oxidative stress KW - pain KW - dog Y1 - 2018 U6 - https://doi.org/10.3389/fvets.2018.00073 SN - 2297-1769 VL - 5 PB - Frontiers Research Foundation CY - Lausanne ER - TY - GEN A1 - Krupkova, Olga A1 - Smolders, Lucas A1 - Wuertz-Kozak, Karin A1 - Cook, James A1 - Pozzi, Antonio T1 - The pathobiology of the meniscus BT - a comparison between the human and dog T2 - Frontiers in Veterinary Science N2 - Serious knee pain and related disability have an annual prevalence of approximately 25% on those over the age of 55 years. As curative treatments for the common knee problems are not available to date, knee pathologies typically progress and often lead to osteoarthritis (OA). While the roles that the meniscus plays in knee biomechanics are well characterized, biological mechanisms underlying meniscus pathophysiology and roles in knee pain and OA progression are not fully clear. Experimental treatments for knee disorders that are successful in animal models often produce unsatisfactory results in humans due to species differences or the inability to fully replicate disease progression in experimental animals. The use of animals with spontaneous knee pathologies, such as dogs, can significantly help addressing this issue. As microscopic and macroscopic anatomy of the canine and human menisci are similar, spontaneous meniscal pathologies in canine patients are thought to be highly relevant for translational medicine. However, it is not clear whether the biomolecular mechanisms of pain, degradation of extracellular matrix, and inflammatory responses are species dependent. The aims of this review are (1) to provide an overview of the anatomy, physiology, and pathology of the human and canine meniscus, (2) to compare the known signaling pathways involved in spontaneous meniscus pathology between both species, and (3) to assess the relevance of dogs with spontaneous meniscal pathology as a translational model. Understanding these mechanisms in human and canine meniscus can help to advance diagnostic and therapeutic strategies for painful knee disorders and improve clinical decision making. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 677 KW - meniscus KW - inflammation KW - oxidative stress KW - pain KW - dog Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-460868 SN - 1866-8364 IS - 677 ER - TY - THES A1 - Radloff, Katrin T1 - The role of the fatty acid profile and its modulation by cytokines in the systemic inflammation in cancer cachexia T1 - O papel e a modulação do perfil de ácidos graxos por citocinas na inflamação da caquexia associada ao câncer T1 - Die Rolle des Fettsäure-Profils und dessen entzündungsbedingten Veränderungen in der Tumorkachexie N2 - Systemic inflammation is a hallmark of cancer cachexia. Among tumor-host interactions, the white adipose tissue (WAT) is an important contributor to inflammation as it suffers morphological reorganization and lipolysis, releasing free fatty acids (FA), bioactive lipid mediators (LM) and pro-inflammatory cytokines, which accentuate the activation of pro-inflammatory signaling pathways and the recruitment of immune cells to the tissue. This project aimed to investigate which inflammatory factors are involved in the local adipose tissue inflammation and what is the influence of such factors upon enzymes involved in FA or LM metabolism in healthy individuals (Control), weight stable gastro-intestinal cancer patients (WSC) and cachectic cancer patients (CC). The results demonstrated that the inflammatory signature of systemic inflammation is different from local adipose tissue inflammation. The systemic inflammation of the cachectic cancer patients was characterized by higher levels of circulating saturated fatty acids (SFA), tumor-necrosis-factor-α (TNF-α), interleukins IL-6, IL-8 and CRP while levels of polyunsaturated fatty acids (PUFAs), especially n3-PUFAs, were lower in CC than in the other groups. In vitro and in adipose tissue explants, pro-inflammatory cytokines and SFAs were shown to increase the chemokines IL-8 and CXCL10 that were found to be augmented in adipose tissue inflammation in CC which was more profound in the visceral adipose tissue (VAT) than in subcutaneous adipose tissue (SAT). Systemic inflammation was negatively associated with the expression of PUFA synthesizing enzymes, though gene and protein expression did hardly differ between groups. The effects of inflammatory factors on enzymes in the whole tissue could have been masked by differentiated modulation of the diverse cell types in the same tissue. In vitro experiments showed that the expression of FA-modifying enzymes such as desaturases and elongases in adipocytes and macrophages was regulated into opposing directions by TNF-α, IL-6, LPS or palmitate. The higher plasma concentration of the pro-resolving LM resolvin D1 in CC cannot compensate the overall inflammatory status and the results indicate that inflammatory cytokines interfere with synthesis pathways of pro-resolving LM. In summary, the data revealed a complex inter-tissue and inter-cellular crosstalk mediated by pro-inflammatory cytokines and lipid compounds enhancing inflammation in cancer cachexia by feed-forward mechanisms. N2 - Systemische Entzündung ist ein grundlegendes Merkmal der Tumorkachexie. Bei den entzündungstreibenden Wechselwirkungen zwischen Tumor und Wirt spielt das weiße Fettgewebe eine besondere Rolle, da es, bedingt durch morphologische Veränderungen und Lipolyse, freie Fettsäuren, bioaktive Lipidmediatoren (LM) und pro-inflammatorische Cytokine freisetzt. Diese verschiedenen Substanzen verstärken die Aktivierung entzündungsfördernder Signalwege und eine Rekrutierung von Immunzellen in das Gewebe. Das Ziel dieser Arbeit war es daher zu untersuchen, welche Faktoren an der Entwicklung der lokalen Fettgewebsentzündung beteiligt sind und wie diese Faktoren Syntheseenzyme von Fettsäuren und Lipidmediatoren beeinflussen könnten. Dazu wurden Plasma und Fettgewebeproben von gesunden Kontrollpersonen (Control) und normalgewichtigen (WSC) sowie kachektischen Magen-Darm-Krebs-Patienten (CC) untersucht. Die Ergebnisse zeigten, dass sich die inflammatorischen Charakteristiken der systemischen Entzündung von denen der lokalen Fettgewebsentzündung unterscheiden. Die systemische Entzündung war gekennzeichnet durch höhere Spiegel gesättigter Fettsäuren (SFA), Tumor-necrosis-factor alpha (TNF-α), Interleukin IL-6, IL-8 und C-reactive protein (CRP) während die Konzentrationen von mehrfachungesättigten Fettsäuren (PUFA) –besonders n3-Fettsäuren- geringer in CC waren als in den anderen Gruppen. In vitro und in ex vivo kultivierten Fettgewebssegmenten konnte gezeigt werden, dass die Inkubation mit pro-inflammatorischen Cytokinen und gesättigten Fettsäuren zu einem Anstieg der Chemokine IL-8 sowie CXCL10 führte. Erhöhte Spiegel dieser Moleküle wurden auch in der Fettgewebsentzündung bei kachektischen Patienten beobachtet, welche im viszeralen Fettgewebe ausgeprägter war als im subkutanen. Systemische Entzündungsmarker waren negativ mit der Expression PUFA-synthetisierender Enzyme assoziiert, obwohl sich Gesamt-mRNA-sowie Proteingehalt kaum zwischen den Studiengruppen unterschieden. Die Effekte von Entzündungsfaktoren auf diese Enzyme im Gesamtgewebe könnten durch eine differenzielle Modulierung in diversen Zelltypen des Gewebes maskiert sein. Denn in in vitro-Experimenten zeigte die Inkubation mit TNF-α, IL-6, LPS oder Palmitat, dass die GeneExpression von Fettsäure-modifizierenden Enzymen wie Desaturasen oder Elongasen in Adipozyten und Makrophagen in entgegengesetzte Richtungen reguliert wird. Die höhere Plasmakonzentration des entzündungslösenden LM Resolvin D1 in CC konnte dem inflammatorischen Zustand nicht entgegenwirken und die Ergebnisse deuten darauf hin, dass inflammatorische Cytokine in die Synthesewege von entzündungslösenden LM eingreifen. Zusammenfassend demonstrieren die Daten das komplexe Zusammenspiel zwischen verschiedenen Geweben und Zelltypen, in dem Cytokine und Lipidverbindungen aus dem Blutkreislauf die Entzündung der Tumorkachexie durch selbst-verstärkende Mechanismen vorantreiben. N2 - A inflamação sistêmica é uma das características que marcam o diagnóstico da caquexia associada ao câncer. Entre as interações tumor-hospedeiro, o tecido adiposo branco contribui à inflamação, uma vez que ele sofre uma reorganização morfológica e lipólise, liberando ácidos graxos livres (AGLs), mediadores lipídicos (LMs) e citocinas pró-inflamatórias, que acentuam a ativação de vias de sinalização pró-inflamatória e o recrutamento de células do sistema imunológico para o tecido. O objetivo deste projeto foi investigar quais fatores inflamatórios sistêmicos estão envolvidos na inflamação do tecido adiposo e qual é a influência desses fatores sobre as enzimas envolvidas no metabolismo dos AGs ou LMs em indivíduos saudáveis (Controle), pacientes com câncer gastrointestinal com peso estável (WSC) e pacientes com câncer e caquexia (CC). Os resultados demonstraram que a resposta inflamatória sistêmica é diferente da resposta encontrada no tecido adiposo. A inflamação sistêmica dos pacientes com câncer e caquexia (CC) foi caracterizada por níveis circulantes mais elevados de ácidos graxos saturados (SFAs), tumor-necrosis-factor-α (TNF-α), Interleukin IL-6, IL-8 e proteina C-reativa (PCR), enquanto os níveis de ácidos graxos poliinsaturados (PUFAs), especialmente n3-PUFAs, foram menores em CC que nos demais grupos. In vitro e em explantes de tecido adiposo, citocinas pró-inflamatórias e SFAs aumentaram a expressão das quimiocinas IL-8 e CXCL10. E tambêm observamos um aumento na expressão destas quimiocinas na inflamação do tecido adiposo no CC, que era mais profundo no tecido adiposo visceral (VAT) quando comparado ao tecido adiposo subcutâneo (SAT). A inflamação sistêmica foi negativamente associada com a expressão de enzimas sintetizadoras dos PUFAs, embora a expressão gênica e protéica mostraram somente pequenas diferencias entre os grupos. Os efeitos dos fatores inflamatórios sobre as enzimas no tecido adiposo podem ter sido mascarados pela modulação diferenciada dos diversos tipos celulares constituintes desse tecido. Experimentos in vitro mostraram que a expressão de enzimas que modificam os AGs, tais como as dessaturases e elongases em adipócitos e macrófagos, foram reguladas em direções opostas por TNF-α, IL-6, LPS e palmitato. Mesmo os pacientes CC demonstrando uma maior concentração plasmática da Resolvina D1, que é um mediador lipídico de resolução da inflamação, ainda assim, a inflamação sistêmica é maior nesses pacientes, e os resultados indicam que as citoquinas inflamatórias interferem com as vias de síntese das LMs da resolução. Concluímos que, os dados revelaram um crosstalk inter-tecidual e intercelular complexo mediado por citocinas pró-inflamatórias e compostos lipídicos que aumentam a inflamação na caquexia associada ao câncer por mecanismos autoregulação. KW - cancer cachexia KW - inflammation KW - adipose tissue KW - cytokines KW - chemokines KW - SFA KW - PUFA Y1 - 2018 ER -