The Experts below are selected from a list of 69756 Experts worldwide ranked by ideXlab platform
Huamei Forsman - One of the best experts on this subject based on the ideXlab platform.
-
staphylococcus aureus derived psmα peptides activate neutrophil fpr2 but lack the ability to mediate β arrestin recruitment and chemotaxis
Journal of Immunology, 2019Co-Authors: Martina Sundqvist, Karin Christenson, Michael Gabl, Claes Dahlgren, Andre Holdfeldt, Karin Jennbacken, Thor C Moller, Huamei ForsmanAbstract:Formyl peptide Receptor 2 (FPR2) is a G protein-coupled pattern recognition Receptor sensing both mitochondrial- and bacterial-derived formylated peptides, including the PSMα toxins secreted by community-associated methicillin-resistant Staphylococcus aureus strains. Similar to many other FPR2 agonistic peptides, nanomolar concentrations of both PSMα2 and PSMα3 activate neutrophils to increase the cytosolic concentration of Ca2+ and release NADPH oxidase-derived reactive oxygen species. In addition, the PSMα peptides induce FPR2 homologous desensitization, actin polymerization, and neutrophil reactivation through a Receptor Cross-Talk mechanism. However, in contrast to conventional FPR2 agonistic peptides, including the host-derived formyl peptide MCT-ND4, we found that the PSMα peptides lacked the ability to recruit β-arrestin and induce neutrophil chemotaxis, supporting the previous notion that β-arrestin translocation is of importance for cell migration. Despite the lack of β-arrestin recruitment, the PSMα peptides induced an FPR2-dependent ERK1/2 phosphorylation and internalization. Furthermore, structure-activity relationship analysis with PSMα2 derivatives revealed critical roles of the first 3 aa linked to N-fMet as well as the C terminus of PSMα2 in promoting FPR2 to recruit β-arrestin. In summary, our data demonstrate a novel neutrophil activation pattern upon FPR2 sensing of PSMα peptides, signified by the ability to induce increased intracellular Ca2+, ERK1/2 phosphorylation, internalization, and NADPH oxidase activity, yet lack of β-arrestin recruitment and neutrophil chemoattraction. These novel features adopted by the PSMα peptides could be of importance for S. aureus virulence and might facilitate identification of new therapeutic strategies for treating S. aureus infections.
-
formyl peptide Receptors in mice and men similarities and differences in recognition of conventional ligands and modulating lipopeptides
Basic & Clinical Pharmacology & Toxicology, 2018Co-Authors: Malene Winther, Claes Dahlgren, Huamei ForsmanAbstract:The pattern recognition formyl peptide Receptors (FPRs) belong to the class of G protein-coupled Receptors (GPCRs), the largest group of cell-surface Receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel Receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, Receptor reactivation and Receptor Cross-Talk. When it comes to allosteric modulators, “tailor-made” lipopeptides (pepducins and lipopeptoids) represent a novel concept of GPCR/FPR regulation. This MiniReview is focused on the basis for recognition of conventional ligands and immunomodulating lipopeptids, novel allosteric modulators for the FPRs, Receptors that are highly expressed by both human and mouse neutrophils. The FPRs play key roles in host defence against microbial infections, tissue homeostasis and the initiation as well as resolution of inflammation but there are both similarities and differences in ligand recognition between mice and men. Thus, identification and functional characterization of activating and inhibiting ligands should provide insights into future design of FPR-based animal models of human diseases and development of therapeutics for treating inflammatory diseases. This article is protected by copyright. All rights reserved.
-
basic characteristics of the neutrophil Receptors that recognize formylated peptides a danger associated molecular pattern generated by bacteria and mitochondria
Biochemical Pharmacology, 2016Co-Authors: Claes Dahlgren, Malene Winther, Michael Gabl, Andre Holdfeldt, Huamei ForsmanAbstract:Proper recruitment and activation of neutrophils to/at sites of infection/inflammation relies largely on the surface expression of chemoattractant Receptors of which a formyl peptide Receptor (FPR1) was the first to be cloned and characterized in more detail. This Receptor displays high affinity for bacterial- or mitochondrial-derived peptides that contain a formylated methionine in the N-terminus. The neutrophil chemoattractant Receptors belong to the group of 7-transmembrane domain Receptors that signal through activation of heterotrimeric G proteins. These Receptors have been shown to be important in host defense against microbial intruders and in regulating inflammatory reactions. The two FPRs (FPR1, FPR2) expressed in neutrophils share significant sequence homology and bind many structurally diverse activating (agonistic) and inhibiting (antagonistic) ligands, ranging from peptides to lipopeptides containing peptide sequences derived from intracellular regions of the FPRs. Recent structural and functional studies of the two neutrophil FPRs have generated important information for our understanding of general pharmacological principles, governing regulation of neutrophil function and inflammation and increased knowledge of more general G-protein coupled Receptor features, such as ligand recognition, biased signaling, allosteric modulation, and a unique Receptor Cross-Talk phenomenon. This article aims to summarize recent discoveries and pharmacological characterization of neutrophil FPRs and to discuss unmet challenges, including recognition by the Receptors of diverse ligands and how biased signals mediate different biological effects.
-
a pepducin derived from the third intracellular loop of fpr2 is a partial agonist for direct activation of this Receptor in neutrophils but a full agonist for cross talk triggered reactivation of fpr2
PLOS ONE, 2014Co-Authors: Michael Gabl, Malene Winther, Claes Dahlgren, Johan Bylund, Sarah Line Skovbakke, Huamei ForsmanAbstract:We recently described a novel Receptor Cross-Talk mechanism in neutrophils, unique in that the signals generated by the PAF Receptor (PAFR) and the ATP Receptor (P2Y2R) transfer formyl peptide Receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Onnheim K, et al., Exp Cell Res, 323∶209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related Receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the Cross-Talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this Receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a Receptor Cross-Talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naive cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy), meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by Receptor Cross-Talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct Receptor activation and Cross-Talk reactivation of FPR2 puts the concept of functional selectivity in focus.
-
a novel Receptor cross talk between the atp Receptor p2y2 and formyl peptide Receptors reactivates desensitized neutrophils to produce superoxide
Experimental Cell Research, 2014Co-Authors: Karin Onnheim, Karin Christenson, Michael Gabl, Joachim C Burbiel, Claes Dahlgren, Johan Bylund, Christa E. Müller, Tudor I Oprea, Huamei ForsmanAbstract:Abstract Neutrophils express several G-protein coupled Receptors (GPCRs) and they cross regulate each other. We described a novel Cross-Talk mechanism in neutrophils, by which signals generated by the Receptor for ATP (P2Y2) reactivate desensitized formyl peptide Receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the Cross-Talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca2+ transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel Cross-Talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.
Claes Dahlgren - One of the best experts on this subject based on the ideXlab platform.
-
staphylococcus aureus derived psmα peptides activate neutrophil fpr2 but lack the ability to mediate β arrestin recruitment and chemotaxis
Journal of Immunology, 2019Co-Authors: Martina Sundqvist, Karin Christenson, Michael Gabl, Claes Dahlgren, Andre Holdfeldt, Karin Jennbacken, Thor C Moller, Huamei ForsmanAbstract:Formyl peptide Receptor 2 (FPR2) is a G protein-coupled pattern recognition Receptor sensing both mitochondrial- and bacterial-derived formylated peptides, including the PSMα toxins secreted by community-associated methicillin-resistant Staphylococcus aureus strains. Similar to many other FPR2 agonistic peptides, nanomolar concentrations of both PSMα2 and PSMα3 activate neutrophils to increase the cytosolic concentration of Ca2+ and release NADPH oxidase-derived reactive oxygen species. In addition, the PSMα peptides induce FPR2 homologous desensitization, actin polymerization, and neutrophil reactivation through a Receptor Cross-Talk mechanism. However, in contrast to conventional FPR2 agonistic peptides, including the host-derived formyl peptide MCT-ND4, we found that the PSMα peptides lacked the ability to recruit β-arrestin and induce neutrophil chemotaxis, supporting the previous notion that β-arrestin translocation is of importance for cell migration. Despite the lack of β-arrestin recruitment, the PSMα peptides induced an FPR2-dependent ERK1/2 phosphorylation and internalization. Furthermore, structure-activity relationship analysis with PSMα2 derivatives revealed critical roles of the first 3 aa linked to N-fMet as well as the C terminus of PSMα2 in promoting FPR2 to recruit β-arrestin. In summary, our data demonstrate a novel neutrophil activation pattern upon FPR2 sensing of PSMα peptides, signified by the ability to induce increased intracellular Ca2+, ERK1/2 phosphorylation, internalization, and NADPH oxidase activity, yet lack of β-arrestin recruitment and neutrophil chemoattraction. These novel features adopted by the PSMα peptides could be of importance for S. aureus virulence and might facilitate identification of new therapeutic strategies for treating S. aureus infections.
-
formyl peptide Receptors in mice and men similarities and differences in recognition of conventional ligands and modulating lipopeptides
Basic & Clinical Pharmacology & Toxicology, 2018Co-Authors: Malene Winther, Claes Dahlgren, Huamei ForsmanAbstract:The pattern recognition formyl peptide Receptors (FPRs) belong to the class of G protein-coupled Receptors (GPCRs), the largest group of cell-surface Receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel Receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, Receptor reactivation and Receptor Cross-Talk. When it comes to allosteric modulators, “tailor-made” lipopeptides (pepducins and lipopeptoids) represent a novel concept of GPCR/FPR regulation. This MiniReview is focused on the basis for recognition of conventional ligands and immunomodulating lipopeptids, novel allosteric modulators for the FPRs, Receptors that are highly expressed by both human and mouse neutrophils. The FPRs play key roles in host defence against microbial infections, tissue homeostasis and the initiation as well as resolution of inflammation but there are both similarities and differences in ligand recognition between mice and men. Thus, identification and functional characterization of activating and inhibiting ligands should provide insights into future design of FPR-based animal models of human diseases and development of therapeutics for treating inflammatory diseases. This article is protected by copyright. All rights reserved.
-
basic characteristics of the neutrophil Receptors that recognize formylated peptides a danger associated molecular pattern generated by bacteria and mitochondria
Biochemical Pharmacology, 2016Co-Authors: Claes Dahlgren, Malene Winther, Michael Gabl, Andre Holdfeldt, Huamei ForsmanAbstract:Proper recruitment and activation of neutrophils to/at sites of infection/inflammation relies largely on the surface expression of chemoattractant Receptors of which a formyl peptide Receptor (FPR1) was the first to be cloned and characterized in more detail. This Receptor displays high affinity for bacterial- or mitochondrial-derived peptides that contain a formylated methionine in the N-terminus. The neutrophil chemoattractant Receptors belong to the group of 7-transmembrane domain Receptors that signal through activation of heterotrimeric G proteins. These Receptors have been shown to be important in host defense against microbial intruders and in regulating inflammatory reactions. The two FPRs (FPR1, FPR2) expressed in neutrophils share significant sequence homology and bind many structurally diverse activating (agonistic) and inhibiting (antagonistic) ligands, ranging from peptides to lipopeptides containing peptide sequences derived from intracellular regions of the FPRs. Recent structural and functional studies of the two neutrophil FPRs have generated important information for our understanding of general pharmacological principles, governing regulation of neutrophil function and inflammation and increased knowledge of more general G-protein coupled Receptor features, such as ligand recognition, biased signaling, allosteric modulation, and a unique Receptor Cross-Talk phenomenon. This article aims to summarize recent discoveries and pharmacological characterization of neutrophil FPRs and to discuss unmet challenges, including recognition by the Receptors of diverse ligands and how biased signals mediate different biological effects.
-
a pepducin derived from the third intracellular loop of fpr2 is a partial agonist for direct activation of this Receptor in neutrophils but a full agonist for cross talk triggered reactivation of fpr2
PLOS ONE, 2014Co-Authors: Michael Gabl, Malene Winther, Claes Dahlgren, Johan Bylund, Sarah Line Skovbakke, Huamei ForsmanAbstract:We recently described a novel Receptor Cross-Talk mechanism in neutrophils, unique in that the signals generated by the PAF Receptor (PAFR) and the ATP Receptor (P2Y2R) transfer formyl peptide Receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Onnheim K, et al., Exp Cell Res, 323∶209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related Receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the Cross-Talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this Receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a Receptor Cross-Talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naive cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy), meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by Receptor Cross-Talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct Receptor activation and Cross-Talk reactivation of FPR2 puts the concept of functional selectivity in focus.
-
a novel Receptor cross talk between the atp Receptor p2y2 and formyl peptide Receptors reactivates desensitized neutrophils to produce superoxide
Experimental Cell Research, 2014Co-Authors: Karin Onnheim, Karin Christenson, Michael Gabl, Joachim C Burbiel, Claes Dahlgren, Johan Bylund, Christa E. Müller, Tudor I Oprea, Huamei ForsmanAbstract:Abstract Neutrophils express several G-protein coupled Receptors (GPCRs) and they cross regulate each other. We described a novel Cross-Talk mechanism in neutrophils, by which signals generated by the Receptor for ATP (P2Y2) reactivate desensitized formyl peptide Receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the Cross-Talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca2+ transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel Cross-Talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.
Marvin C Gershengorn - One of the best experts on this subject based on the ideXlab platform.
-
thyroid stimulating hormone tsh insulin like growth factor 1 igf1 Receptor cross talk in human cells
Current Opinion in Endocrine and Metabolic Research, 2018Co-Authors: Christine C Krieger, Susanne Neumann, Sarah J Morgan, Marvin C GershengornAbstract:Thyroid stimulating hormone and insulin-like growth factor 1 Receptors (TSHRs and IGF1Rs, respectively) interact leading to additive or synergistic stimulation of cellular responses. Recent findings provide evidence that the interaction between TSHRs and IGF1Rs is similar to that described for other G protein-coupled Receptors and Receptor tyrosine kinases. These types of interactions occur at or proximal to the Receptors and are designated "Receptor Cross-Talk." Herein, we describe our studies in human thyrocytes, human retro-orbital fibroblasts from Graves' orbitopathy patients and a model cell line that support the concept of TSHR/IGF1R Cross-Talk. We also discuss how Receptor Cross-Talk is involved in stimulation by a monoclonal TSHR-stimulating antibody and how targeting both Receptors may lead to novel treatments of Graves' orbitopathy.
-
tsh igf 1 Receptor cross talk in graves ophthalmopathy pathogenesis
The Journal of Clinical Endocrinology and Metabolism, 2016Co-Authors: Christine C Krieger, George J Kahaly, Bernice Marcussamuels, Susanne Neumann, Robert F Place, Carmine Bevilacqua, Brent S Abel, Monica C Skarulis, Marvin C GershengornAbstract:Context: The TSH Receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 Receptor (IGF-1R) autoantibodies also play a role. Objective: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. Design/Setting/Participants: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. Main Outcome Measures: Hyaluronan (hyalu...
-
bidirectional tsh and igf 1 Receptor cross talk mediates stimulation of hyaluronan secretion by graves disease immunoglobins
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Christine C Krieger, Bernice Marcussamuels, Susanne Neumann, Robert F Place, Marvin C GershengornAbstract:Context: There is no pathogenetically linked medical therapy for Graves' ophthalmopathy (GO). Lack of animal models and conflicting in vitro studies have hindered the development of such therapy. Recent reports propose that Graves' Igs bind to and activate thyrotropin Receptors (TSHRs) and IGF-1 Receptors (IGF-1Rs) on cells in orbital fat, stimulating hyaluronan (HA) secretion, a component of GO. Objective: The objective of the study was to investigate potential cross talk between TSHRs and IGF-1Rs in the pathogenesis of GO using a sensitive HA assay. Design/Setting/Participants: Orbital fibroblasts from GO patients were collected in an academic clinical practice and cultured in a research laboratory. Cells were treated with TSH, IGF-1, and a monoclonal Graves' Ig M22. Main Outcome Measures: HA was measured by a modified ELISA. Results: Simultaneous activation by TSH and IGF-1 synergistically increased HA secretion from 320 ± 52 for TSH and 430 ± 65 μg/mL for IGF-1 alone, to 1300 ± 95 μg/mL. IGF-1 shifted...
Marie-christine Chagnon - One of the best experts on this subject based on the ideXlab platform.
-
Estrogen Receptor α and aryl hydrocarbon Receptor Cross-Talk in a transfected hepatoma cell line (HepG2) exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin
Toxicology Reports, 2014Co-Authors: Manuela Göttel, Ludovic Le Corre, Coralie Dumont, Dieter Schrenk, Marie-christine ChagnonAbstract:The prototype dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert anti-estrogenic effects via activation of the aryl hydrocarbon Receptor (AhR) by interfering with the regulation of oestrogen homeostasis and the estrogen Receptor α (ERα) signalling pathway. The AhR/ER Cross-Talk is considered to play a crucial role in TCDD- and E2-dependent mechanisms of carcinogenesis, though the concerted mechanism of action in the liver is not yet elucidated. The present study investigated TCDD's impact on the transcriptional Cross-Talk between AhR and ERα and its modulation by 17β-estradiol (E2) in the human hepatoma cell line HepG2, which is AhR-responsive but ERα-negative. Transient transfection assays with co-transfection of hERα and supplementation of Receptor antagonists showed anti-estrogenic action of TCDD via down-regulation of E2-induced ERα signaling. In contrast, enhancement of AhR signaling dependent on ERα was observed providing evidence for increased cytochrome P450 (CYP) induction to promote E2 metabolism. However, relative mRNA levels of major E2-metabolizing CYP1A1 and 1B1 and the main E2-detoxifying catechol-O-methyltransferase were not affected by the co-treatments. This study provides new evidence of a TCDD-activated AhR-mediated molecular AhR/ERα Cross-Talk mechanism at transcriptional level via indirect inhibition of ERα and enhanced transcriptional activity of AhR in HepG2 cells.
Christine C Krieger - One of the best experts on this subject based on the ideXlab platform.
-
thyroid stimulating hormone tsh insulin like growth factor 1 igf1 Receptor cross talk in human cells
Current Opinion in Endocrine and Metabolic Research, 2018Co-Authors: Christine C Krieger, Susanne Neumann, Sarah J Morgan, Marvin C GershengornAbstract:Thyroid stimulating hormone and insulin-like growth factor 1 Receptors (TSHRs and IGF1Rs, respectively) interact leading to additive or synergistic stimulation of cellular responses. Recent findings provide evidence that the interaction between TSHRs and IGF1Rs is similar to that described for other G protein-coupled Receptors and Receptor tyrosine kinases. These types of interactions occur at or proximal to the Receptors and are designated "Receptor Cross-Talk." Herein, we describe our studies in human thyrocytes, human retro-orbital fibroblasts from Graves' orbitopathy patients and a model cell line that support the concept of TSHR/IGF1R Cross-Talk. We also discuss how Receptor Cross-Talk is involved in stimulation by a monoclonal TSHR-stimulating antibody and how targeting both Receptors may lead to novel treatments of Graves' orbitopathy.
-
tsh igf 1 Receptor cross talk in graves ophthalmopathy pathogenesis
The Journal of Clinical Endocrinology and Metabolism, 2016Co-Authors: Christine C Krieger, George J Kahaly, Bernice Marcussamuels, Susanne Neumann, Robert F Place, Carmine Bevilacqua, Brent S Abel, Monica C Skarulis, Marvin C GershengornAbstract:Context: The TSH Receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 Receptor (IGF-1R) autoantibodies also play a role. Objective: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. Design/Setting/Participants: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. Main Outcome Measures: Hyaluronan (hyalu...
-
bidirectional tsh and igf 1 Receptor cross talk mediates stimulation of hyaluronan secretion by graves disease immunoglobins
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Christine C Krieger, Bernice Marcussamuels, Susanne Neumann, Robert F Place, Marvin C GershengornAbstract:Context: There is no pathogenetically linked medical therapy for Graves' ophthalmopathy (GO). Lack of animal models and conflicting in vitro studies have hindered the development of such therapy. Recent reports propose that Graves' Igs bind to and activate thyrotropin Receptors (TSHRs) and IGF-1 Receptors (IGF-1Rs) on cells in orbital fat, stimulating hyaluronan (HA) secretion, a component of GO. Objective: The objective of the study was to investigate potential cross talk between TSHRs and IGF-1Rs in the pathogenesis of GO using a sensitive HA assay. Design/Setting/Participants: Orbital fibroblasts from GO patients were collected in an academic clinical practice and cultured in a research laboratory. Cells were treated with TSH, IGF-1, and a monoclonal Graves' Ig M22. Main Outcome Measures: HA was measured by a modified ELISA. Results: Simultaneous activation by TSH and IGF-1 synergistically increased HA secretion from 320 ± 52 for TSH and 430 ± 65 μg/mL for IGF-1 alone, to 1300 ± 95 μg/mL. IGF-1 shifted...
