Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

The Physiology of Glucagon-like Peptide 1

Consensus statement on the pathology of IgG4-related disease

IgG4-related disease.

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135 mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10 cells/high powered field of biopsy sample Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz’s disease (MD) and kidney disease (KD) In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists

Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011

Estrogen receptors (ERs) act by regulating transcriptional processes. The classical mechanism of ER action involves estrogen binding to receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as estrogen response elements (EREs) located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus. In addition, membrane-associated ERs mediate nongenomic actions of estrogens, which can lead both to altered functions of proteins in the cytoplasm and to regulation of gene expression. The latter two mechanisms of ER action enable a broader range of genes to be regulated than the range that can be regulated by the classical mechanism of ER action alone. This review surveys our knowledge about the molecular mechanism by which ERs regulate the expression of genes that do not contain EREs, and it gives examples of the ways in which the genomic and nongenomic actions of ERs on target genes converge. Genomic and nongenomic actions of ERs that do not depend on EREs influence the physiology of many target tissues, and thus, increasing our understanding of the molecular mechanisms behind these actions is highly relevant for the development of novel drugs that target specific receptor actions.

Mechanisms of Estrogen Receptor Signaling: Convergence of Genomic and Nongenomic Actions on Target Genes

Background Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract. Methods We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjogren's syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor. Results The median serum IgG4 concentration in the patients ...

https://www.nejm.org/doi/pdf/10.1056/NEJM200103083441005

High serum IgG4 concentrations in patients with sclerosing pancreatitis.

https://www.gastrojournal.org/article/S0016-5085(02)68241-1/pdf

HLA DRB1*0405-DQB1*0401 haplotype is associated with autoimmune pancreatitis in the Japanese population

We previously reported that afferent signals of the rat hepatic vagus increased upon intraportal appearance of insulinotropic hormone glucagon-like peptide-1(7-36) amide (GLP-1), but not glucose-dependent insulinotropic polypeptide (GIP). To obtain molecular evidence for the vagal chemoreception of GLP-1, the concept derived from those electrophysiological observations, receptor gene expressions of GLP-1 and GIP in the rat nodose ganglion were examined by means of reverse transcriptase-mediated polymerase chain reaction (RT-PCR) and Northern blot analysis. Gene expression of the GLP-1 receptor was clearly detected by both RT-PCR and Northern blot analysis. In situ hybridization study confirmed that the expression occurs in neuronal cells of the ganglion. As to the GIP receptor, RT-PCR amplified the gene transcript faintly though Northern blot analysis failed to detect any messages. However, semi-quantitative RT-PCR revealed that the ratio of the gene expression level of the GIP receptor to that of the GLP-1 receptor was less than 1:250, indicating that receptor gene expression of GIP is practically negligible in the ganglion. Additionally, an equal level of GLP-1 receptor gene expressions between left- and right-side ganglia was evidenced by semi-quantitative RT-PCR, implying possible extrahepatic occurrence of vagal GLP-1 reception in addition to the reception through the hepatic vagus (originating from the left-side ganglion). The present results offer, for the first time, the molecular basis for the vagal chemoreception of GLP-1 via its specific receptor.

Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells

Although the bone morphogenetic proteins (BMPs) are multifunctional proteins, implantation of osteogenic BMPs such as BMP-2 and BMP-7 at an osseous or extraosseous site results in bone and cartilage formation. These molecules are soluble, local-acting signaling proteins, which bind to specific receptors on the surface of the cell. The receptors then transduce the signal via a group of proteins called Smads, which in turn activate particular genes. In vivo, these BMPs act primarily as differentiation factors, turning responsive mesenchymal cells into cartilage- and bone-forming cells. A summary of the in vitro and in vivo studies suggests that implantation of these BMPs stimulates cells from the soft and hard tissues (e.g., muscle, bone marrow, periosteum) to become bone, and in some cases, cartilage forming cells. The activity of BMPs is tightly controlled at many levels. The tissue-specific transcription factor (basic helix-loop-helix factor) and its binding sequence (E-box) together play a critical role in deciding the expression of BMPs. Outside the cell, soluble inhibitory proteins such as noggin, chordin, and follistatin can bind certain of the BMPs and inhibit their binding to cell surface receptors. Inside the cell, the activity of BMPs is controlled through the combination of signal-transducing and inhibitory Smad proteins. Bone morphogenetic proteins can upregulate expression of the inhibitory Smad proteins. These Smads are phosphorylated and translocate into the nucleus, where they regulate the transcription of target genes together with other transcription factors including PEBP2alphaA/Cbfa1. Cooperation between PEBP2alphaA/Cbfa1 and BMP-activated Smad (Smad1/5) in the nucleus induces the expression of the genes related to the osteoblast phenotype. In addition, a number of negative regulators of BMP action exist within the nucleus. All of these regulatory mechanisms together cause the bone-induction process to be controlled tightly and self-limiting. Thus, bone induction is observed only locally at the site of BMP and matrix implantation, as defined by the volume of matrix, and it is limited temporally only to the time when the BMP is present.

Mechanism for the action of bone morphogenetic proteins and regulation of their activity.

Delta is a major transmembrane ligand for Notch receptor that mediates numerous cell fate decisions. The Notch signaling pathway has long been thought to be mono-directional, because ligands for Notch were generally believed to be unable to transmit signals into the cells expressing them. However, we showed here that Notch also supplies signals to neighboring mouse neural stem cells (NSCs). To investigate the Notch-Delta signaling pathway in a bi-directional manner, we analyzed functional roles of the intracellular domain of mouse Delta like protein 1 (Dll1IC). In developing mouse NSCs, Dll1IC, which is released from cell membrane by proteolysis, is present in the nucleus. Furthermore, we screened for transcription factors that bind to Dll1IC and demonstrated that Dll1IC binds specifically to transcription factors involved in TGF-beta/Activin signaling--Smad2, Smad3 and Smad4--and enhances Smad-dependent transcription. In addition, the results of the present study indicated that over-expression of Dll1IC in embryonic carcinoma P19 cells induced neurons, and this induction was blocked by SB431542, which is a specific inhibitor of TGF-beta/Activin signaling. These observations strongly suggested that Dll1IC mediates TGF-beta/Activin signaling through binding to Smads and plays an important role for bi-directional Notch-Delta signaling pathway.

/pdf/the-delta-intracellular-domain-mediates-tgf-b-activin-345xecvw4x.pdf

The Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch–Delta signaling pathway

Kohzo Nakayama

Papers

High serum IgG4 concentrations in patients with sclerosing pancreatitis.

HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population

Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells

Mechanism for the action of bone morphogenetic proteins and regulation of their activity.

The Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch–Delta signaling pathway