Control of the expression of inflammatory response genes

2003 ◽  
Vol 70 ◽  
pp. 95-106 ◽  
Author(s):  
Jeremy Saklatvala ◽  
Jonathan Dean ◽  
Andrew Clark
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Inflammatory Response ◽  
Mapk Pathway ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Matrix Metalloproteinase 1 ◽  
Inflammatory Stimuli ◽  
Mitogen Activated Protein

The expression of genes involved in the inflammatory response is controlled both transcriptionally and post-transcriptionally. Primary inflammatory stimuli, such as microbial products and the cytokines interleukin-1 (IL-1) and tumour necrosis factor α (TNFα), act through receptors of either the Toll and IL-1 receptor (TIR) family or the TNF receptor family. These cause changes in gene expression by activating four major intracellular signalling pathways that are cascades of protein kinases: namely the three mitogen-activated protein kinase (MAPK) pathways, and the pathway leading to activation of the transcription factor nuclear factor ϰB (NFϰB). The pathways directly activate and induce the expression of a limited set of transcription factors which promote the transcription of inflammatory response genes. Many of the mRNAs are unstable, and are stabilized by the p38 MAPK pathway. Instability is mediated by clusters of the AUUUA motif in the 3″ untranslated regions of the mRNAs. Control of mRNA stability provides a means of increasing the amplitude of a response and allows rapid adjustment of mRNA levels. Not all mRNAs stabilized by p38 contain AUUUA clusters; for example, matrix metalloproteinase-1 and -3 mRNAs lack these clusters, but are stabilized. Inflammatory gene expression is inhibited by glucocorticoids. These suppress MAPK signalling by inducing a MAPK phosphatase. This may be a significant mechanism additional to that by which the glucocorticoid receptor interferes with transcription factors.

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

2007 ◽  
Vol 293 (5) ◽  
pp. F1556-F1563 ◽  
Author(s):  
Frank Y. Ma ◽  
Greg H. Tesch ◽  
Richard A. Flavell ◽  
Roger J. Davis ◽  
David J. Nikolic-Paterson
Keyword(s):  
Inflammatory Response ◽  
P38 Mapk ◽  
Renal Injury ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Direct Role ◽  
Mitogen Activated Protein ◽  
Early Inflammatory Response ◽  
Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

TNF-α and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms

2001 ◽  
Vol 281 (6) ◽  
pp. G1405-G1412 ◽  
Author(s):  
T. Suzuki ◽  
E. Grand ◽  
C. Bowman ◽  
J. L. Merchant ◽  
A. Todisco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Interleukin 1 ◽  
Mitogen Activated Protein Kinase ◽  
G Cells ◽  
Kinase C ◽  
Tnf Α ◽  
Mitogen Activated Protein

Helicobacter pyloriand proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-α and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-α and IL-1 significantly increased gastrin mRNA in canine G cells to 181 ± 18% and 187 ± 28% of control, respectively, after 24 h of treatment. TNF-α and IL-1 stimulated gastrin promoter activity to a maximal level of 285 ± 12% and 415 ± 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-α and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.

scholarly journals Thrombopoietin Induces HOXA9 Nuclear Transport in Immature Hematopoietic Cells: Potential Mechanism by Which the Hormone Favorably Affects Hematopoietic Stem Cells

2004 ◽  
Vol 24 (15) ◽  
pp. 6751-6762 ◽  
Author(s):  
Keita Kirito ◽  
Norma Fox ◽  
Kenneth Kaushansky
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Hematopoietic Stem Cells ◽  
Nuclear Translocation ◽  
Hematopoietic Cells ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Hematopoietic Stem ◽  
Nuclear Localization Signals ◽  
Mitogen Activated Protein

ABSTRACT Members of the homeobox family of transcription factors are major regulators of hematopoiesis. Overexpression of either HOXB4 or HOXA9 in primitive marrow cells enhances the expansion of hematopoietic stem cells (HSCs). However, little is known of how expression or function of these proteins is regulated during hematopoiesis under physiological conditions. In our previous studies we demonstrated that thrombopoietin (TPO) enhances levels of HOXB4 mRNA in primitive hematopoietic cells (K. Kirito, N. Fox, and K. Kaushansky, Blood 102:3172-3178, 2003). To extend our studies, we investigated the effects of TPO on HOXA9 in this same cell population. Although overall levels of the transcription factor were not affected, we found that TPO induced the nuclear import of HOXA9 both in UT-7/TPO cells and in primitive Sca-1+/c-kit+/Gr-1− hematopoietic cells in a mitogen-activated protein kinase-dependent fashion. TPO also controlled MEIS1 expression at mRNA levels, at least in part due to phosphatidylinositol 3-kinase activation. Collectively, TPO modulates the function of HOXA9 by leading to its nuclear translocation, likely mediated by effects on its partner protein MEIS1, and potentially due to two newly identified nuclear localization signals. Our data suggest that TPO controls HSC development through the regulation of multiple members of the Hox family of transcription factors through multiple mechanisms.

scholarly journals Paeoniflorin and Albiflorin Attenuate Neuropathic Pain via MAPK Pathway in Chronic Constriction Injury Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Jianyu Zhou ◽  
Linyuan Wang ◽  
Jingxia Wang ◽  
Chun Wang ◽  
Zhihui Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Mapk Pathway ◽  
Biological Activities ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Necrosis Factor

Neuropathic pain remains as the most frequent cause of suffering and disability around the world. The isomers paeoniflorin (PF) and albiflorin (AF) are major constituents extracted from the roots ofPaeonia (P.) lactifloraPall. Neuroprotective effect of PF has been demonstrated in animal models of neuropathologies. However, only a few studies are related to the biological activities of AF and no report has been published on analgesic properties of AF about neuropathic pain to date. The aim of this study was to compare the effects of AF and PF against CCI-induced neuropathic pain in rat and explore the underlying mechanism. We had found that both PF and AF could inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK) pathway in spinal microglia and subsequent upregulated proinflammatory cytokines (interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α)). AF further displayed remarkable effects on inhibiting the activation of astrocytes, suppressing the overelevated expression of phosphorylation of c-Jun N-terminal kinases (p-JNK) in astrocytes, and decreasing the content of chemokine CXCL1 in the spinal cord. These results suggest that both PF and AF are potential therapeutic agents for neuropathic pain, which merit further investigation.

Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts

2008 ◽  
Vol 412 (3) ◽  
pp. 435-445 ◽  
Author(s):  
Maja Jensen ◽  
Jane Palsgaard ◽  
Rehannah Borup ◽  
Pierre de Meyts ◽  
Lauge Schäffer
Keyword(s):  
Gene Expression ◽  
Insulin Receptor ◽  
Mapk Pathway ◽  
Receptor Activation ◽  
Mitogen Activated Protein Kinase ◽  
Single Chain ◽  
Therapeutic Implications ◽  
Insulin Mimetic ◽  
Mitogen Activated Protein

Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications.

scholarly journals Transcriptional Coregulation by the Cell Integrity Mitogen-Activated Protein Kinase Slt2 and the Cell Cycle Regulator Swi4

2001 ◽  
Vol 21 (19) ◽  
pp. 6515-6528 ◽  
Author(s):  
Kristin Baetz ◽  
Jason Moffat ◽  
Jennifer Haynes ◽  
Michael Chang ◽  
Brenda Andrews
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Wall ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Cell Integrity ◽  
Mitogen Activated Protein

ABSTRACT In Saccharomyces cerevisiae, the heterodimeric transcription factor SBF (for SCB binding factor) is composed of Swi4 and Swi6 and activates gene expression at the G1/S-phase transition of the mitotic cell cycle. Cell cycle commitment is associated not only with major alterations in gene expression but also with highly polarized cell growth; the mitogen-activated protein kinase (MAPK) Slt2 is required to maintain cell wall integrity during periods of polarized growth and cell wall stress. We describe experiments aimed at defining the regulatory pathway involving the cell cycle transcription factor SBF and Slt2-MAPK. Gene expression assays and chromatin immunoprecipitation experiments revealed Slt2-dependent recruitment of SBF to the promoters of the G1 cyclinsPCL1 and PCL2 after activation of the Slt2-MAPK pathway. We performed DNA microarray analysis and identified other genes whose expression was reduced in both SLT2and SWI4 deletion strains. Genes that are sensitive to both Slt2 and Swi4 appear to be uniquely regulated and reveal a role for Swi4, the DNA-binding component of SBF, which is independent of the regulatory subunit Swi6. Some of the Swi4- and Slt2-dependent genes do not require Swi6 for either their expression or for Swi4 localization to their promoters. Consistent with these results, we found a direct interaction between Swi4 and Slt2. Our results establish a new Slt2-dependent mode of Swi4 regulation and suggest roles for Swi4 beyond its prominent role in controlling cell cycle transcription.

Signal transduction events involved in TPA downregulation of SP-A gene expression

2004 ◽  
Vol 286 (6) ◽  
pp. L1210-L1219 ◽  
Author(s):  
Olga L. Miakotina ◽  
Jeanne M. Snyder
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Surfactant Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Novel Isoforms

Surfactant protein A (SP-A), the most abundant pulmonary surfactant protein, plays a role in innate host defense and blocks the inhibitory effects of serum proteins on surfactant surface tension-lowering properties. SP-A mRNA and protein are downregulated by phorbol esters (TPA) via inhibition of gene transcription. We evaluated the TPA signaling pathways involved in SP-A inhibition in a lung cell line, H441 cells. TPA caused sustained phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK, and c-Jun-NH2-terminal kinase. An inhibitor of conventional and novel isoforms of protein kinase C (PKC) and two inhibitors of p44/42 MAPK kinase partially or completely blocked the inhibitory effects of TPA on SP-A mRNA levels. In contrast, inhibitors of conventional PKC-α and -β, stress-activated protein kinases, protein phosphatases, protein kinase A, and the phosphatidylinositol 3-kinase pathway had no effect on the TPA-mediated inhibition of SP-A mRNA. TPA also stimulated the synthesis of c-Jun mRNA and protein in a time-dependent manner. Inhibitors of the p44/42 MAPK signaling pathway and PKC blocked the TPA-mediated phosphorylation of p44/42 MAPK and the increase in c-Jun mRNA. We conclude that TPA inhibits SP-A gene expression via novel isoforms of PKC, the p44/42 MAPK pathway, and the activator protein-1 complex.

Distinct roles for extracellular-signal-regulated protein kinase (ERK) mitogen-activated protein kinases and phosphatidylinositol 3-kinase in the regulation of Mcl-1 synthesis

2001 ◽  
Vol 356 (2) ◽  
pp. 473-480 ◽  
Author(s):  
Kathryn M. SCHUBERT ◽  
Vincent DURONIO
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Family Members ◽  
Protein Translation ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphatidylinositol 3

Alterations in the expression of various Bcl-2 family members may act as one means by which a cell's survival may be regulated. The mechanism by which cytokines regulate expression of Bcl-2 family members was examined in the haemopoietic cell line TF-1. Cytokine-induced Mcl-1 protein expression was shown to be controlled through a pathway dependent upon phosphatidylinositol 3-kinase (PI 3-kinase). The cytokine-induced increase in mRNA transcription was not dependent upon PI 3-kinase, thus dissociating the immediate-early transcription factors responsible for Mcl-1 transcription from the PI 3-kinase signalling pathway. In contrast, Mcl-1 mRNA levels were dependent upon MEK [mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated protein kinase kinase] activation, suggesting a role for the Ras/MEK/MAPK pathway in Mcl-1 transcription. Activation of PI 3-kinase was shown to be necessary to stimulate Mcl-1 protein translation. This was not due to any effect on prolonging the half-life of the protein. Finally, the lipid second messenger ceramide was shown to cause a reduction in Mcl-1 protein translation, probably via its ability to inhibit protein kinase B activation, providing further clues regarding the death-inducing effect of this lipid.

Systems analysis of MAPK signal transduction

2008 ◽  
Vol 45 ◽  
pp. 95-108 ◽  
Author(s):  
Nils Blüthgen ◽  
Stefan Legewie
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Mapk Pathway ◽  
Experimental Studies ◽  
Mitogen Activated Protein Kinase ◽  
Cell Fate Decisions ◽  
Biological Responses ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Extracellular Stimuli

For more than a decade, the MAPK (mitogen-activated protein kinase) cascade has been studied using mathematical modelling and quantitative experimentation [1]. The MAPK cascade relays the presence of extracellular stimuli such as growth hormones to the nucleus and controls the expression of hundreds of genes. MAPKs control major cell fate decisions such as proliferation, differentiation and apoptosis, mainly by inducing alterations in gene expression. In this chapter, we discuss how systems biology analysis provides insights into the functioning of this cascade. We show how this pathway assists the cell in responding properly to extracellular cues by filtering out sub-threshold stimuli, while efficiently transmitting physiologically relevant inputs. Several different receptors signal through the MAPK pathway even though they elicit opposite biological responses, thus raising the question of how specificity is achieved in MAPK signalling. Experimental studies revealed that specific biological responses are encoded by quantitative aspects of the MAPK signal such as amplitude or duration. We discuss mechanisms that enable the pathway to generate quantitatively different signals, and also explain how different signals are interpreted by the downstream gene expression machinery.

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