BACKGROUND: Ron receptor tyrosine kinase signaling in macrophages, including Kupffer cells and alveolar macrophages,suppresses endotoxin-induced proinflammatory cytokine/chemokine production. Further, we have also ide...BACKGROUND: Ron receptor tyrosine kinase signaling in macrophages, including Kupffer cells and alveolar macrophages,suppresses endotoxin-induced proinflammatory cytokine/chemokine production. Further, we have also identified genes from Ron replete and Ron deplete livers that were differentially expressed during the progression of liver inflammation associated with acute liver failure in mice by microarray analyses.While important genes and signaling pathways have been identified downstream of Ron signaling during progression of inflammation by this approach, the precise role that Ron receptor plays in regulating the transcriptional landscape in macrophages, and particular in isolated Kupffer cells, has still not been investigated.METHODS: Kupffer cells were isolated from wild-type(TK+/+)and Ron tyrosine kinase deficient(TK-/-) mice. Ex vivo, the cells were treated with lipopolysaccharide(LPS) in the presence or absence of the Ron ligand, hepatocyte growth factor-like protein(HGFL). Microarray and qRT-PCR analyses were utilized to identify alterations in gene expression between genotypes.RESULTS: Microarray analyses identified genes expressed differentially in TK+/+ and TK-/- Kupffer cells basally as well as after HGFL and LPS treatment. Interestingly, our studies identified Mefv, a gene that codes for the anti-inflammatory protein pyrin, as an HGFL-stimulated Ron-dependent gene.Moreover, lipocalin 2, a proinflammatory gene, which is induced by LPS, was significantly suppressed by HGFL treatment.Microarray results were validated by qRT-PCR studies on Kupffer cells treated with LPS and HGFL.CONCLUSION: The studies herein suggest a novel mechanism whereby HGFL-induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages.展开更多
Objective: The aim of our study was to evaluate the clinical features, to define the frequency of mutation type, to assess genotype-phenotype correlation and the response to colchicine in childhood-onset Familial Medi...Objective: The aim of our study was to evaluate the clinical features, to define the frequency of mutation type, to assess genotype-phenotype correlation and the response to colchicine in childhood-onset Familial Mediterranean fever (FMF) in Lebanon. Methods: The characteristics of 550 children, presenting with FMF symptoms between January 2003 and January 2013 and having a positive Mediterranean fever gene (MEFV gene) mutation, were prospectively investigated. The clinical and genetic characteristics as well as the response to colchicine and its side effects were studied in 321 FMF children. The mutations were correlated with clinical presentation and disease severity. Results: Out of the 321 patients (183 males and 138 females), abdominal pain was the most common presenting feature documented in 84.7%. Mutational analysis detected simple heterozygotes, compound heterozygotes and homozygotes in 56.4%, 30.9% and 11.2% patients respectively. The most frequent mutation was M694V (37.2%), followed by E148Q mutation (27.4%). 71% patients received colchicine therapy;only 33.3% of them showed complete response. Genotype-phenotype correlation showed that M694V followed by E148Q was associated with moderate to severe disease form (71.6% and 62.7% respectively, P = 0.005). There was no association between mutation type and colchicine response. Conclusion: The most important features were the predominance of the M694V and E148Q. The M694V subgroup, followed by E148Q subgroup had a high disease severity score. Our data indicate an enhanced expression of the disease with E148Q mutation.展开更多
Background: Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder that associated with different genetic mutations. Frequency of clinical manifestation differs according to age group, geographic r...Background: Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder that associated with different genetic mutations. Frequency of clinical manifestation differs according to age group, geographic region and ethnic population. Objectives: To study the clinical manifestation of FMF in relation to genotype (M680I, M694V, M694I and V726A). Result: The main presentation of studied group was abdominal pain 65.9% (203), followed by fever 60.4% (186) patients. (Mutation M694V) was the commonest 47.6% (297), followed by (Mutation V726A) in 32.8% (169%), then (Mutation M6802) in 23.4% (121) lastly (Mutation M6941) was in 22.1% (114) patients. Fever was highly associated with mutation (V729A) and it was statistically significant (*p value 0.047). Conclusion: Abdominal pain and fever were the most common manifestation of FMF patients. (Mutation M694V), (Mutation V726A) were the most detected mutation. Third age group;fever was associated with genetic mutation (V726A), abdominal pain with (M6941).展开更多
Pyrin,encoded by MEFV gene,is conserved in humans and mice.Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever(FMF).Pyrin can interact with the inflammasome a...Pyrin,encoded by MEFV gene,is conserved in humans and mice.Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever(FMF).Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells,but the physiological function of Pyrin has been unknown for many years.Here we summarize previous studies of Pyrin function under the context of FMF and immunity,and discuss a recent study demonstrating that Pyrin forms an inflammasome complex for caspase-1 activation in innate immunity.Pyrin inflammasome detects inactivating modifications of host Rho GTPases by diverse bacterial toxins and infections,including Clostridium difficile glucosylating cytotoxin Tcd B,FIC-domain adenylyltransferase effectors from Vibrio parahaemolyticus and Histophilus somni,ADP-ribosylating Clostridium botulinum C3 toxin as well as Burkholderia cenocepacia infection.The mode of Pyrin action,i.e.,sensing pathogen virulence activity rather than directly recognizing a microbial molecule,represents a new paradigm in innate immunity.展开更多
Introduction:Plasminogen(PLG)deficiency is an ultrarare disease.The reported manifestations in literature were linked to pseudomembrane formation and mucosal surfaces inflammation.Recently,PLG,its activa-tors and its ...Introduction:Plasminogen(PLG)deficiency is an ultrarare disease.The reported manifestations in literature were linked to pseudomembrane formation and mucosal surfaces inflammation.Recently,PLG,its activa-tors and its receptors have gained more attention in inflammation regulatory processes,including the release of proinflammatory signaling molecules,and thus its role is believed to have clinical implications beyond what has been known.Case Report:We present a child with recurrent fever who,although managed initially as familial Mediterranean fever,later on,developed a constellation of findings that were not explained by a classified autoinflammatory disease.Genetic testing revealed a novel homozygous PLG mutation(PLG:c.466G>A:p.D156N)and a likely benign heterozygous MEFV gene variant.We propose that the PLG mutation is responsible for the clinical manifestations,which may or may not be exacerbated by the coexistence of the MEFV variant.A relationship between the PLG pathway,inflammation,and FMF severity has been addressed recently in several studies.Conclusion:This report highlights the recently recognized role of the PLG pathway in inflammatory diseases and describes a potentially new presenta-tion of PLG pathogenesis.Further studies are needed to confirm this finding and allow for a more definitive conclusion.展开更多
基金supported in part by grants from the Public Health Services Grants CA125379NIH P30 DK078392 from the National Institutes of Health,Veteran's Administration VA1001BX00080312POST12040055 from the American Heart Association Great Rivers Affiliate
文摘BACKGROUND: Ron receptor tyrosine kinase signaling in macrophages, including Kupffer cells and alveolar macrophages,suppresses endotoxin-induced proinflammatory cytokine/chemokine production. Further, we have also identified genes from Ron replete and Ron deplete livers that were differentially expressed during the progression of liver inflammation associated with acute liver failure in mice by microarray analyses.While important genes and signaling pathways have been identified downstream of Ron signaling during progression of inflammation by this approach, the precise role that Ron receptor plays in regulating the transcriptional landscape in macrophages, and particular in isolated Kupffer cells, has still not been investigated.METHODS: Kupffer cells were isolated from wild-type(TK+/+)and Ron tyrosine kinase deficient(TK-/-) mice. Ex vivo, the cells were treated with lipopolysaccharide(LPS) in the presence or absence of the Ron ligand, hepatocyte growth factor-like protein(HGFL). Microarray and qRT-PCR analyses were utilized to identify alterations in gene expression between genotypes.RESULTS: Microarray analyses identified genes expressed differentially in TK+/+ and TK-/- Kupffer cells basally as well as after HGFL and LPS treatment. Interestingly, our studies identified Mefv, a gene that codes for the anti-inflammatory protein pyrin, as an HGFL-stimulated Ron-dependent gene.Moreover, lipocalin 2, a proinflammatory gene, which is induced by LPS, was significantly suppressed by HGFL treatment.Microarray results were validated by qRT-PCR studies on Kupffer cells treated with LPS and HGFL.CONCLUSION: The studies herein suggest a novel mechanism whereby HGFL-induced Ron receptor activation promotes the expression of anti-inflammatory genes while inhibiting genes involved in inflammation with a net effect of diminished inflammation in macrophages.
文摘Objective: The aim of our study was to evaluate the clinical features, to define the frequency of mutation type, to assess genotype-phenotype correlation and the response to colchicine in childhood-onset Familial Mediterranean fever (FMF) in Lebanon. Methods: The characteristics of 550 children, presenting with FMF symptoms between January 2003 and January 2013 and having a positive Mediterranean fever gene (MEFV gene) mutation, were prospectively investigated. The clinical and genetic characteristics as well as the response to colchicine and its side effects were studied in 321 FMF children. The mutations were correlated with clinical presentation and disease severity. Results: Out of the 321 patients (183 males and 138 females), abdominal pain was the most common presenting feature documented in 84.7%. Mutational analysis detected simple heterozygotes, compound heterozygotes and homozygotes in 56.4%, 30.9% and 11.2% patients respectively. The most frequent mutation was M694V (37.2%), followed by E148Q mutation (27.4%). 71% patients received colchicine therapy;only 33.3% of them showed complete response. Genotype-phenotype correlation showed that M694V followed by E148Q was associated with moderate to severe disease form (71.6% and 62.7% respectively, P = 0.005). There was no association between mutation type and colchicine response. Conclusion: The most important features were the predominance of the M694V and E148Q. The M694V subgroup, followed by E148Q subgroup had a high disease severity score. Our data indicate an enhanced expression of the disease with E148Q mutation.
文摘Background: Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder that associated with different genetic mutations. Frequency of clinical manifestation differs according to age group, geographic region and ethnic population. Objectives: To study the clinical manifestation of FMF in relation to genotype (M680I, M694V, M694I and V726A). Result: The main presentation of studied group was abdominal pain 65.9% (203), followed by fever 60.4% (186) patients. (Mutation M694V) was the commonest 47.6% (297), followed by (Mutation V726A) in 32.8% (169%), then (Mutation M6802) in 23.4% (121) lastly (Mutation M6941) was in 22.1% (114) patients. Fever was highly associated with mutation (V729A) and it was statistically significant (*p value 0.047). Conclusion: Abdominal pain and fever were the most common manifestation of FMF patients. (Mutation M694V), (Mutation V726A) were the most detected mutation. Third age group;fever was associated with genetic mutation (V726A), abdominal pain with (M6941).
基金supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institutethe Beijing Scholar Program to Shao Feng+2 种基金Other financial supports include the National Basic Research Program of China(2012CB518700),the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB08020202)National Science Fund for Distinguished Young Scholars(31225002)to Shao Feng
文摘Pyrin,encoded by MEFV gene,is conserved in humans and mice.Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever(FMF).Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells,but the physiological function of Pyrin has been unknown for many years.Here we summarize previous studies of Pyrin function under the context of FMF and immunity,and discuss a recent study demonstrating that Pyrin forms an inflammasome complex for caspase-1 activation in innate immunity.Pyrin inflammasome detects inactivating modifications of host Rho GTPases by diverse bacterial toxins and infections,including Clostridium difficile glucosylating cytotoxin Tcd B,FIC-domain adenylyltransferase effectors from Vibrio parahaemolyticus and Histophilus somni,ADP-ribosylating Clostridium botulinum C3 toxin as well as Burkholderia cenocepacia infection.The mode of Pyrin action,i.e.,sensing pathogen virulence activity rather than directly recognizing a microbial molecule,represents a new paradigm in innate immunity.
文摘Introduction:Plasminogen(PLG)deficiency is an ultrarare disease.The reported manifestations in literature were linked to pseudomembrane formation and mucosal surfaces inflammation.Recently,PLG,its activa-tors and its receptors have gained more attention in inflammation regulatory processes,including the release of proinflammatory signaling molecules,and thus its role is believed to have clinical implications beyond what has been known.Case Report:We present a child with recurrent fever who,although managed initially as familial Mediterranean fever,later on,developed a constellation of findings that were not explained by a classified autoinflammatory disease.Genetic testing revealed a novel homozygous PLG mutation(PLG:c.466G>A:p.D156N)and a likely benign heterozygous MEFV gene variant.We propose that the PLG mutation is responsible for the clinical manifestations,which may or may not be exacerbated by the coexistence of the MEFV variant.A relationship between the PLG pathway,inflammation,and FMF severity has been addressed recently in several studies.Conclusion:This report highlights the recently recognized role of the PLG pathway in inflammatory diseases and describes a potentially new presenta-tion of PLG pathogenesis.Further studies are needed to confirm this finding and allow for a more definitive conclusion.
