BIOMAT Database Logo BIOMAT Database Logo

Lipopolysaccharide (LPS) directly suppresses growth hormone receptor (GHR) expression through MyD88-dependent and -independent Toll-like receptor-4/MD2 complex signaling pathways. 2007

Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

BACKGROUND Sepsis is associated with growth hormone (GH) insensitivity and in the intact animal the major surface component of the bacterial cell wall, lipopolysaccharide (LPS), inhibits GH receptor (GHR) gene expression. The prevailing explanation for LPS-induced effects on the GHR promoter is that this effect is indirect via generation of cytokines. Our recent studies demonstrate that saturated free fatty acids (FFAs) inhibit the activity of the murine GHR promoter. Saturated FFAs are an essential component of the lipid A moiety of LPS required for biological activity of LPS. OBJECTIVE LPS directly modulates the activity of the dominant GHR promoter via interaction with Toll-like receptor(s) (TLR)/MD2 complex and activation of cognate signaling pathway(s). RESULTS In transient transfection experiments with RAW 264.7 cells which express endogenous TLR4 and MD2, LPS treatment inhibited GHR promoter activity. Co-transfection of dominant negative TLR4 abrogated this effect on GHR promoter activity. In HEK 293T cells, which are devoid of endogenous TLR4 or MD2, ectopic expression of TLR4 and MD2 resulted in LPS-induced inhibition of the GHR promoter activity. The inhibition of GHR promoter activity was demonstrable by 5-6h after exposure to LPS and persisted at 24h. Fatty-acid free LPS failed to elicit a similar effect on the GHR promoter and the effect of LPS was abrogated by Polymyxin B. The essential role of the cofactor MD2 on the effect of LPS on the GHR promoter was established in experiments using ectopic expression of wild type and mutant MD2. Cotransfection of CD14 in these cells failed to alter the effect of LPS on the activity of the GHR promoter. Analysis of cell culture supernatant excluded the possibility that the effect of LPS was secondary to release of cytokines from the transfected cells. The effect of LPS on the endogenous GHR promoter activity and protein expression was confirmed in F442A preadipocyte cells. In HEK 293T cells, ectopic expression of mutant MyD88 or mutant TRIF abrogated the effect of LPS on the GHR promoter, suggesting that the effect of LPS on the GHR promoter was via both MyD88-dependent and -independent pathways. CONCLUSIONS LPS acts through both MyD88-dependent and -independent TLR4 signaling pathways to directly inhibit GHR gene expression. Our results establish a novel cytokine-independent mechanism for decrease in GHR expression in bacterial sepsis.

UI MeSH Term Description Entries
D008070 Lipopolysaccharides Lipid-containing polysaccharides which are endotoxins and important group-specific antigens. They are often derived from the cell wall of gram-negative bacteria and induce immunoglobulin secretion. The lipopolysaccharide molecule consists of three parts: LIPID A, core polysaccharide, and O-specific chains (O ANTIGENS). When derived from Escherichia coli, lipopolysaccharides serve as polyclonal B-cell mitogens commonly used in laboratory immunology. (From Dorland, 28th ed) Lipopolysaccharide,Lipoglycans
D011401 Promoter Regions, Genetic DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes. rRNA Promoter,Early Promoters, Genetic,Late Promoters, Genetic,Middle Promoters, Genetic,Promoter Regions,Promoter, Genetic,Promotor Regions,Promotor, Genetic,Pseudopromoter, Genetic,Early Promoter, Genetic,Genetic Late Promoter,Genetic Middle Promoters,Genetic Promoter,Genetic Promoter Region,Genetic Promoter Regions,Genetic Promoters,Genetic Promotor,Genetic Promotors,Genetic Pseudopromoter,Genetic Pseudopromoters,Late Promoter, Genetic,Middle Promoter, Genetic,Promoter Region,Promoter Region, Genetic,Promoter, Genetic Early,Promoter, rRNA,Promoters, Genetic,Promoters, Genetic Middle,Promoters, rRNA,Promotor Region,Promotors, Genetic,Pseudopromoters, Genetic,Region, Genetic Promoter,Region, Promoter,Region, Promotor,Regions, Genetic Promoter,Regions, Promoter,Regions, Promotor,rRNA Promoters
D011986 Receptors, Somatotropin Cell surface proteins that bind GROWTH HORMONE with high affinity and trigger intracellular changes influencing the behavior of cells. Activation of growth hormone receptors regulates amino acid transport through cell membranes, RNA translation to protein, DNA transcription, and protein and amino acid catabolism in many cell types. Many of these effects are mediated indirectly through stimulation of the release of somatomedins. Growth Hormone Receptors,Receptors, Growth Hormone,Somatomammotropin Receptors,Somatotropin Receptors,Growth Hormone Receptor,Receptor, Growth Hormone,Receptors, Somatomammotropin,Somatomammotropin Receptor,Somatotropin Receptor,Hormone Receptor, Growth,Hormone Receptors, Growth
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D046912 Multiprotein Complexes Macromolecular complexes formed from the association of defined protein subunits. Macromolecular Protein Complexes,Complexes, Macromolecular Protein,Complexes, Multiprotein,Protein Complexes, Macromolecular
D051197 Toll-Like Receptor 4 A pattern recognition receptor that interacts with LYMPHOCYTE ANTIGEN 96 and LIPOPOLYSACCHARIDES. It mediates cellular responses to GRAM-NEGATIVE BACTERIA. TLR4 Receptor,Toll-4 Receptor,Receptor, TLR4,Toll 4 Receptor,Toll Like Receptor 4

Related Publications

Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Differential induction of the toll-like receptor 4-MyD88-dependent and -independent signaling pathways by endotoxins.
May 2005, Infection and immunity,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Sialyl residues modulate LPS-mediated signaling through the Toll-like receptor 4 complex.
January 2012, PloS one,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
AKT1 distinctively suppresses MyD88-depenedent and TRIF-dependent Toll-like receptor signaling in a kinase activity-independent manner.
March 2018, Cellular signalling,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Toll-like receptor-mediated tyrosine phosphorylation of paxillin via MyD88-dependent and -independent pathways.
March 2003, European journal of immunology,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway.
February 2002, Journal of immunology (Baltimore, Md. : 1950),
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Beyond MyD88 and TRIF Pathways in Toll-Like Receptor Signaling.
January 2014, Frontiers in immunology,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)- and Lectin-Stimulated Toll-like Receptor 4 (TLR4) Signaling.
June 2017, Journal of medicinal chemistry,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Bacterial lipopolysaccharide signaling through Toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity.
July 2003, Journal of immunology (Baltimore, Md. : 1950),
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Toll-like receptor 2-independent and MyD88-dependent gene expression in the mouse brain.
January 2009, Journal of innate immunity,
Prapai Dejkhamron, and Jamuna Thimmarayappa, and Kateryna Kotlyarevska, and Jinhong Sun, and Chunxia Lu, and Erin L Bonkowski, and Lee A Denson, and Ram K Menon
Statins inhibit toll-like receptor 4-mediated lipopolysaccharide signaling and cytokine expression.
September 2008, Pharmacogenetics and genomics,
Copied contents to your clipboard!