Both endogenous and exogenous proteases have been implicated in allergic airway diseases. Though recent studies have demonstrated the role of airway epithelial cells in pathophysiology of allergic diseases, the mechanisms of epithelial activation remain largely unknown. Recently published study (Kale and Arora, 2014) focused on elucidating the role of serine protease activity of Per a 10 on airway epithelial activation and to gain an insight into possible mechanism. We found that airway epithelial activation by Per a 10 is dependent on its serine protease activity. Further we showed that this activation is PAR2 dependent and leads to Ca 2+ mobilisation. This Research Highlight discusses the findings of our recent study and active research endeavors.
内源性和外源性蛋白酶都与过敏性气道疾病有关。虽然最近的研究已经证明气道上皮细胞在变态反应性疾病的病理生理中的作用，但上皮细胞活化的机制仍不清楚。最近发表的研究(Kale和Arora, 2014)专注于阐明Per a 10丝氨酸蛋白酶活性在气道上皮活化中的作用，并深入了解可能的机制。我们发现，Per a 10对气道上皮的激活依赖于其丝氨酸蛋白酶的活性。进一步，我们发现这种激活是PAR2依赖性的，并导致ca2 +的动员。本研究重点讨论了我们最近的研究成果和积极的研究努力。
{"title":"A cockroach derived serine protease allergen activates airway epithelial cells via PAR2 receptors","authors":"S. Kale, N. Arora","doi":"10.14800/ICS.501","DOIUrl":"https://doi.org/10.14800/ICS.501","url":null,"abstract":"Both endogenous and exogenous proteases have been implicated in allergic airway diseases. Though recent studies have demonstrated the role of airway epithelial cells in pathophysiology of allergic diseases, the mechanisms of epithelial activation remain largely unknown. Recently published study (Kale and Arora, 2014) focused on elucidating the role of serine protease activity of Per a 10 on airway epithelial activation and to gain an insight into possible mechanism. We found that airway epithelial activation by Per a 10 is dependent on its serine protease activity. Further we showed that this activation is PAR2 dependent and leads to Ca 2+ mobilisation. This Research Highlight discusses the findings of our recent study and active research endeavors.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85600099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Jono, S. Shinriki, Jianying Guo, Jian-Dong Li, Y. Ando
Cylindromatosis (CYLD) was originally identified as a tumor suppressor, because loss of its function causes a benign human tumor. In the past, multitude of efforts have been made toward elucidating the biological features of CYLD, and uncovered not only its multiple functions as deubiquitinase, but also the clinical significance of CYLD in a wide variety of diseases. At present, dysregulation of CYLD by loss of its expression is believed to play key roles in a multiple of pathological processes, including tumor cell proliferation, survival, and inflammatory responses by regulating their specific cell signaling pathway. Recently, we discovered that loss of CYLD expression in hypoxic regions of human glioblastoma multiforme (GBM), the most aggressive brain tumor, suggesting the clinical significance of CYLD in the pathogenesis of GBM. Here, we reviewed the diverse biological features and clinical significance of CYLD, particularly focusing on the roles of CYLD as a critical regulator of hypoxia-mediated inflammation in GBM.
{"title":"CYLD: a critical regulator of hypoxia-mediated inflammation in tumors","authors":"H. Jono, S. Shinriki, Jianying Guo, Jian-Dong Li, Y. Ando","doi":"10.14800/ICS.479","DOIUrl":"https://doi.org/10.14800/ICS.479","url":null,"abstract":"Cylindromatosis (CYLD) was originally identified as a tumor suppressor, because loss of its function causes a benign human tumor. In the past, multitude of efforts have been made toward elucidating the biological features of CYLD, and uncovered not only its multiple functions as deubiquitinase, but also the clinical significance of CYLD in a wide variety of diseases. At present, dysregulation of CYLD by loss of its expression is believed to play key roles in a multiple of pathological processes, including tumor cell proliferation, survival, and inflammatory responses by regulating their specific cell signaling pathway. Recently, we discovered that loss of CYLD expression in hypoxic regions of human glioblastoma multiforme (GBM), the most aggressive brain tumor, suggesting the clinical significance of CYLD in the pathogenesis of GBM. Here, we reviewed the diverse biological features and clinical significance of CYLD, particularly focusing on the roles of CYLD as a critical regulator of hypoxia-mediated inflammation in GBM.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90406175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marie-Luise Lubos, Stefanie Norkowski, A. Stolle, Ü. Langel, M. A. Schmidt, C. Rüter
Previous studies identified the effector protein YopM of Yersinia enterocolitica as a novel bacterial cell-penetrating protein. YopM’s ability to translocate across the host cell plasma membrane independently of Yersinia’s type III secretion system (T3SS) is mediated by its two N-terminal α-helices. The SspH1 effector protein of Salmonella typhimurium shares significant homology in sequence and structure with YopM, which prompted us to investigate potential cell-penetrating abilities of this effector protein. For this, we recombinantly expressed SspH1 in Escherichia coli and analyzed a potential T3SS-independent translocation of the protein by cell fractionation of HeLa cells, immunofluorescence microscopy and FACS analyses. The functionality of the recombinant protein as an E3 ubiquitin- ligase was determined using in vitro -ubiquitination assays. Additionally, an effect of the recombinant protein on the expression of pro-inflammatory cytokines was analyzed by quantitative real time PCR. In this study, we could show that the SspH1 effector protein of Salmonella typhimurium is able to translocate autonomously into eukaryotic cells without requiring additional factors. Furthermore, we could show that recombinant SspH1 is a functional E3 ubiquitin ligase that is able to undergo auto-ubiquitination following T3SS-independent translocation and to reduce the expression of Interleukin-8 in IL-1β stimulated cells.
{"title":"Analysis of T3SS-independent autonomous internalization of the bacterial effector protein SspH1 from Salmonella typhimurium","authors":"Marie-Luise Lubos, Stefanie Norkowski, A. Stolle, Ü. Langel, M. A. Schmidt, C. Rüter","doi":"10.14800/ICS.423","DOIUrl":"https://doi.org/10.14800/ICS.423","url":null,"abstract":"Previous studies identified the effector protein YopM of Yersinia enterocolitica as a novel bacterial cell-penetrating protein. YopM’s ability to translocate across the host cell plasma membrane independently of Yersinia’s type III secretion system (T3SS) is mediated by its two N-terminal α-helices. The SspH1 effector protein of Salmonella typhimurium shares significant homology in sequence and structure with YopM, which prompted us to investigate potential cell-penetrating abilities of this effector protein. For this, we recombinantly expressed SspH1 in Escherichia coli and analyzed a potential T3SS-independent translocation of the protein by cell fractionation of HeLa cells, immunofluorescence microscopy and FACS analyses. The functionality of the recombinant protein as an E3 ubiquitin- ligase was determined using in vitro -ubiquitination assays. Additionally, an effect of the recombinant protein on the expression of pro-inflammatory cytokines was analyzed by quantitative real time PCR. In this study, we could show that the SspH1 effector protein of Salmonella typhimurium is able to translocate autonomously into eukaryotic cells without requiring additional factors. Furthermore, we could show that recombinant SspH1 is a functional E3 ubiquitin ligase that is able to undergo auto-ubiquitination following T3SS-independent translocation and to reduce the expression of Interleukin-8 in IL-1β stimulated cells.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82542471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In a previous study, we reported a class of spirooxindole-pyranopyrimidine compounds that exhibited broad spectrum anti-cancer activity. In a most recent study, we found that one of these compounds, JP-8g, also showed potent in vivo anti-inflammatory activity. In vitro and in vivo experiments suggested that JP-8g exerts this activity through nitric oxide (NO) signaling pathway. Herein, we discuss the potential of the use of these compounds as anti-inflammatory agents. The new data in this study also suggested that NF-kB signaling pathway is not involved in the anti-inflammatory activity of JP-8g.
{"title":"Spirooxindoles, a potential novel class of anti-inflammatory agents","authors":"Jia Liu, Yulong Sun, Xuehong Zhang, Li Xiaolei, Yanjing Wu, Yiqing Wang, Xianxing Jiang","doi":"10.14800/ICS.372","DOIUrl":"https://doi.org/10.14800/ICS.372","url":null,"abstract":"In a previous study, we reported a class of spirooxindole-pyranopyrimidine compounds that exhibited broad spectrum anti-cancer activity. In a most recent study, we found that one of these compounds, JP-8g, also showed potent in vivo anti-inflammatory activity. In vitro and in vivo experiments suggested that JP-8g exerts this activity through nitric oxide (NO) signaling pathway. Herein, we discuss the potential of the use of these compounds as anti-inflammatory agents. The new data in this study also suggested that NF-kB signaling pathway is not involved in the anti-inflammatory activity of JP-8g.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85790443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nuclear receptor peroxisome proliferative activated receptor gamma (PPARg) is a prominent targeted molecule in ovarian syndrome. Rosiglitazone, a potent drug administered during Polycystic ovarian syndrome (PCOS), executes its effects through this receptor. However, the exact mechanism through which Rosiglitazone induces PPARg and mediates its action in ovary is not well documented. In the present study, we delineated the signaling pathway for Rosiglitazone action in granulosa cell functioning by using buffalo granulosa cell model. Experiments were performed in serum free primary buffalo granulosa cell culture when cells were follicle stimulating hormone (FSH) responsive with pre-ovulatory phenotype. The cells were incubated with Rosiglitazone alone or in combination with FSH (25 ng/ml) and IGF-1(50 ng/ml). Results showed that Rosiglitazone (25 µM) inhibited FSH and insulin like growth factor-1 (IGF-1) induced granulosa cell proliferation, aromatase, GATA-4, IGF-1 mRNA and oestradiol-17β production. Western blot analysis of total cell lysates revealed that Rosiglitazone intervene with the FSH and IGF-1 signaling by decreasing p-Akt. In addition, Rosiglitazone was found to up-regulate PPAR g and (PTEN) in granulosa cells. PPARg antagonist (GW9662) had no effect on p-Akt level, as well as on steroidogenesis. PTEN inhibitor bpV(pic) revived Akt phosphorylation to the level of control. In conclusion, the present study demonstrated that Rosiglitazone attenuated FSH and IGF-1 induced downstream PI3K/Akt pathway mediated granulosa cell function ( proliferation and steroidogenesis) involving PPARg and PTEN . The elucidated signaling pathway and participating molecules, PPARg and PTEN, could be potential targets while developing novel molecules in PCOS management and fertility regulation
{"title":"Rosiglitazone suppresses FSH and IGF-1 induced downstream PI3K/Akt pathway mediated granulosa cell function involving PPARg and PTEN: Potential targets of fertility regulation","authors":"I. Sharma, Dheer Singh","doi":"10.14800/ICS.262","DOIUrl":"https://doi.org/10.14800/ICS.262","url":null,"abstract":"Nuclear receptor peroxisome proliferative activated receptor gamma (PPARg) is a prominent targeted molecule in ovarian syndrome. Rosiglitazone, a potent drug administered during Polycystic ovarian syndrome (PCOS), executes its effects through this receptor. However, the exact mechanism through which Rosiglitazone induces PPARg and mediates its action in ovary is not well documented. In the present study, we delineated the signaling pathway for Rosiglitazone action in granulosa cell functioning by using buffalo granulosa cell model. Experiments were performed in serum free primary buffalo granulosa cell culture when cells were follicle stimulating hormone (FSH) responsive with pre-ovulatory phenotype. The cells were incubated with Rosiglitazone alone or in combination with FSH (25 ng/ml) and IGF-1(50 ng/ml). Results showed that Rosiglitazone (25 µM) inhibited FSH and insulin like growth factor-1 (IGF-1) induced granulosa cell proliferation, aromatase, GATA-4, IGF-1 mRNA and oestradiol-17β production. Western blot analysis of total cell lysates revealed that Rosiglitazone intervene with the FSH and IGF-1 signaling by decreasing p-Akt. In addition, Rosiglitazone was found to up-regulate PPAR g and (PTEN) in granulosa cells. PPARg antagonist (GW9662) had no effect on p-Akt level, as well as on steroidogenesis. PTEN inhibitor bpV(pic) revived Akt phosphorylation to the level of control. In conclusion, the present study demonstrated that Rosiglitazone attenuated FSH and IGF-1 induced downstream PI3K/Akt pathway mediated granulosa cell function ( proliferation and steroidogenesis) involving PPARg and PTEN . The elucidated signaling pathway and participating molecules, PPARg and PTEN, could be potential targets while developing novel molecules in PCOS management and fertility regulation","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79023171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Foxa2 [The forkhead box transcription factor-2; also known as HNF3B(hepatocyte nuclear factors-3), or TCF3B(transcription factor-3b) ] [Costa, 1989 #64], is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells lining conducting airways and in alveolar type Ⅱ cells in the development and mature lung. Foxa2 plays critical roles in lung development, which is required for normal lung maturation, surfactant protein and lipid synthesis, epithelial differentiation, and cross talking between epithelium and innate immune. Foxa2 can determine gene expression and cell fate in the lung, and is required for the suppression of Th2 immunity, mucus production, and goblet cell metaplasia in the developing lung in a process determined in part by its regulation of the Cysteinyl leukotriene (CysLT) pathway. Recent studies have implicated that Foxa2 is a suppressor of lung cancer. This review will summarize the role of Foxa2 in lung development, pulmonary diseases, and also the possible signaling pathways regulated by Foxa2.
{"title":"The forkhead box transcription factor-2 (Foxa2) and lung disease","authors":"Xiaoju Tang, F. Luo","doi":"10.14800/ICS.231","DOIUrl":"https://doi.org/10.14800/ICS.231","url":null,"abstract":"Foxa2 [The forkhead box transcription factor-2; also known as HNF3B(hepatocyte nuclear factors-3), or TCF3B(transcription factor-3b) ] [Costa, 1989 #64], is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells lining conducting airways and in alveolar type Ⅱ cells in the development and mature lung. Foxa2 plays critical roles in lung development, which is required for normal lung maturation, surfactant protein and lipid synthesis, epithelial differentiation, and cross talking between epithelium and innate immune. Foxa2 can determine gene expression and cell fate in the lung, and is required for the suppression of Th2 immunity, mucus production, and goblet cell metaplasia in the developing lung in a process determined in part by its regulation of the Cysteinyl leukotriene (CysLT) pathway. Recent studies have implicated that Foxa2 is a suppressor of lung cancer. This review will summarize the role of Foxa2 in lung development, pulmonary diseases, and also the possible signaling pathways regulated by Foxa2.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78500910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-dependent transcription factor that is involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Despite decades of research, the role of PPARδ in inflammation and colorectal cancer remains unclear and somewhat controversial. Our recent work presented the first genetic evidence demonstrating that PPARδ is required for chronic colonic inflammation and colitis-associated carcinogenesis. We also found that a PPARδ downstream pathway, namely the COX-2-derived PGE2 signaling, mediated crosstalk between tumor epithelial cells and macrophages to promote chronic inflammation and colitis-associated tumor genesis. In this brief review, we summarize recent studies on the role of PPARδ in inflammatory bowel disease (IBD) and colorectal cancer (CRC) and highlight recent advances in our understanding of how PPARδ and COX-2-drevided PGE2 signaling coordinately promote chronic colonic inflammation and colitis-associate tumorigenesis. Elucidating the role of PPARδ in inflammation and CRC may provide a rationale for development of PPARδ antagonists as new therapeutic agents in treatment of IBD and CRC.
{"title":"PPARδ and PGE<sub>2</sub> signaling pathways communicate and connect inflammation to colorectal cancer.","authors":"Dingzhi Wang, Raymond N DuBois","doi":"10.14800/ics.338","DOIUrl":"https://doi.org/10.14800/ics.338","url":null,"abstract":"<p><p>The nuclear hormone receptor peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-dependent transcription factor that is involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Despite decades of research, the role of PPARδ in inflammation and colorectal cancer remains unclear and somewhat controversial. Our recent work presented the first genetic evidence demonstrating that PPARδ is required for chronic colonic inflammation and colitis-associated carcinogenesis. We also found that a PPARδ downstream pathway, namely the COX-2-derived PGE<sub>2</sub> signaling, mediated crosstalk between tumor epithelial cells and macrophages to promote chronic inflammation and colitis-associated tumor genesis. In this brief review, we summarize recent studies on the role of PPARδ in inflammatory bowel disease (IBD) and colorectal cancer (CRC) and highlight recent advances in our understanding of how PPARδ and COX-2-drevided PGE<sub>2</sub> signaling coordinately promote chronic colonic inflammation and colitis-associate tumorigenesis. Elucidating the role of PPARδ in inflammation and CRC may provide a rationale for development of PPARδ antagonists as new therapeutic agents in treatment of IBD and CRC.</p>","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539244/pdf/nihms688834.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33934902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyaluronan (HA, an extracellular matrix glycosaminoglycan) has been reported to have a variety of biological activities, including regulation of inflammation. While high molecular weight HA (HMW HA) is recognized to be anti-inflammatory, the activity of low molecular weight HA (LMW HA, the degradation catabolite of hyaluronidase) in inflammation is less clear. Because of reagent contamination of both hyaluronidase and HA used in many studies, many reported aspects of the associated biology need reinvestigation. There are many reports which have shown that LMW HA is pro-inflammatory; however, some recent publications raised serious doubts that LMW HA and hyaluronidase PH20 are not pro-inflammatory. Endotoxin and other contaminants in the reagents used in previous reports (i.e., bovine testicular hyaluronidase [BTH] Hyal type I-S and IV-S from Sigma) may be responsible for the observed inflammation. Further investigation has shown that the most purified BTH (type VI-S from Sigma) contains no endotoxin, but has substantial level of peptidoglycan, which is also pro-inflammatory. Caution should be taken when conducting studies of inflammation using HA and hyaluronidase that may contain endotoxin and peptidoglycan, as well as other pro-inflammatory contaminants. We have characterized HA affinity to its receptor CD44. While HMW HA binds to CD44 strongly, LMW HA degraded by PH20 hyaluronidase does not bind to CD44 on the cell surface. This may explain the observation that recombinant human hyaluronidase PH20 (rHuPH20) inhibits leukocyte migration upon inflammatory stimulation by interrupting CD44 interaction with HA, mediated by HMW HA. PEGPH20, a pegylated rHuPH20, has the same inhibitory activity on leukocyte transmigration as rHuPH20. Further investigation of leukocyte-inhibiting activity of rHuPH20 may reveal further clinical applications, such as wound healing and arthritis. Another report which is difficult to understand is that the ultra-high molecular weight HA produced by naked mole rat hyaluronan synthase-2 (nmrHAS2) contributes to cancer resistance, probably due to its specific anti-inflammatory activity. In our study, nmrHAS2 is cancer-promoting in human cancer cells, to a similar extent as human HAS2. The proposed cancer resistant activity of nmrHAS2 may apply selectively to its host animal species, the naked mole rat.
{"title":"Characterization of hyaluronan, hyaluronidase PH20, and HA synthase HAS2 in inflammation and cancer","authors":"Zhongdong Huang, Chunmei Zhao, A. Radi","doi":"10.14800/ICS.306","DOIUrl":"https://doi.org/10.14800/ICS.306","url":null,"abstract":"Hyaluronan (HA, an extracellular matrix glycosaminoglycan) has been reported to have a variety of biological activities, including regulation of inflammation. While high molecular weight HA (HMW HA) is recognized to be anti-inflammatory, the activity of low molecular weight HA (LMW HA, the degradation catabolite of hyaluronidase) in inflammation is less clear. Because of reagent contamination of both hyaluronidase and HA used in many studies, many reported aspects of the associated biology need reinvestigation. There are many reports which have shown that LMW HA is pro-inflammatory; however, some recent publications raised serious doubts that LMW HA and hyaluronidase PH20 are not pro-inflammatory. Endotoxin and other contaminants in the reagents used in previous reports (i.e., bovine testicular hyaluronidase [BTH] Hyal type I-S and IV-S from Sigma) may be responsible for the observed inflammation. Further investigation has shown that the most purified BTH (type VI-S from Sigma) contains no endotoxin, but has substantial level of peptidoglycan, which is also pro-inflammatory. Caution should be taken when conducting studies of inflammation using HA and hyaluronidase that may contain endotoxin and peptidoglycan, as well as other pro-inflammatory contaminants. We have characterized HA affinity to its receptor CD44. While HMW HA binds to CD44 strongly, LMW HA degraded by PH20 hyaluronidase does not bind to CD44 on the cell surface. This may explain the observation that recombinant human hyaluronidase PH20 (rHuPH20) inhibits leukocyte migration upon inflammatory stimulation by interrupting CD44 interaction with HA, mediated by HMW HA. PEGPH20, a pegylated rHuPH20, has the same inhibitory activity on leukocyte transmigration as rHuPH20. Further investigation of leukocyte-inhibiting activity of rHuPH20 may reveal further clinical applications, such as wound healing and arthritis. Another report which is difficult to understand is that the ultra-high molecular weight HA produced by naked mole rat hyaluronan synthase-2 (nmrHAS2) contributes to cancer resistance, probably due to its specific anti-inflammatory activity. In our study, nmrHAS2 is cancer-promoting in human cancer cells, to a similar extent as human HAS2. The proposed cancer resistant activity of nmrHAS2 may apply selectively to its host animal species, the naked mole rat.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73595398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The common gamma chain (γc) is the central signaling unit for the γc cytokine receptor family. γc cytokine signaling is mainly regulated by cytokine-specific receptor alpha chain expression levels but not γc expression levels. Here we will highlight that a soluble form of γc (sγc) expression, which is generated by alternative splicing, impairs naive T cell survival and promotes inflammation in a manner of inhibiting IL-7 and IL-2 signaling, representatively. Furthermore, sγc expression is significantly enhanced upon T cell activation. sγc enhances in vitro and in vivo Th17 differentiation through dampening of IL-2 signal, and sγc-overexpressing mice are consequently more susceptible to EAE. Therefore, sγc is a novel immunoregulator that control T cell biology by regulation of γc cytokine signaling.
{"title":"The advent of soluble common gamma chain rocks the T cell world: A novel therapeutic target for autoimmune diseases","authors":"Byunghyuk Lee, Changwan Hong","doi":"10.14800/ICS.310","DOIUrl":"https://doi.org/10.14800/ICS.310","url":null,"abstract":"The common gamma chain (γc) is the central signaling unit for the γc cytokine receptor family. γc cytokine signaling is mainly regulated by cytokine-specific receptor alpha chain expression levels but not γc expression levels. Here we will highlight that a soluble form of γc (sγc) expression, which is generated by alternative splicing, impairs naive T cell survival and promotes inflammation in a manner of inhibiting IL-7 and IL-2 signaling, representatively. Furthermore, sγc expression is significantly enhanced upon T cell activation. sγc enhances in vitro and in vivo Th17 differentiation through dampening of IL-2 signal, and sγc-overexpressing mice are consequently more susceptible to EAE. Therefore, sγc is a novel immunoregulator that control T cell biology by regulation of γc cytokine signaling.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77225059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D. Felício, D. S. Pereira, A. M. Assumpção, F. Jesus-Moraleida, B. Z. Queiroz, J. P. Silva, Naysa Maciel de Brito Rosa, João M. D. Dias, L. Pereira
Multiple inter-related factors that contribute to the development and progression of sarcopenia in the elderly. Sarcopenia is enhanced by immunosenescence, in which the induction and expression of inflammatory mediators such as IL-6 and TNF-α increase significantly. High levels of plasma cytokines are a predictor of mortality and morbidly in the elderly and have a catabolic effect on muscle proteins. Our studies show that there is no a cutoff point to predict adverse physical and functional outcomes, the data found are conflicting. More research is needed to clarify the role of systemic inflammation in muscle and functional performance in elderly women.
{"title":"Systemic inflammation and physical function in community elderly women","authors":"D. Felício, D. S. Pereira, A. M. Assumpção, F. Jesus-Moraleida, B. Z. Queiroz, J. P. Silva, Naysa Maciel de Brito Rosa, João M. D. Dias, L. Pereira","doi":"10.14800/ICS.368","DOIUrl":"https://doi.org/10.14800/ICS.368","url":null,"abstract":"Multiple inter-related factors that contribute to the development and progression of sarcopenia in the elderly. Sarcopenia is enhanced by immunosenescence, in which the induction and expression of inflammatory mediators such as IL-6 and TNF-α increase significantly. High levels of plasma cytokines are a predictor of mortality and morbidly in the elderly and have a catabolic effect on muscle proteins. Our studies show that there is no a cutoff point to predict adverse physical and functional outcomes, the data found are conflicting. More research is needed to clarify the role of systemic inflammation in muscle and functional performance in elderly women.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85073123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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