Cross-interactions of Two p38 Mitogen-activated Protein (MAP) Kinase Inhibitors and Two Cholecystokinin (CCK) Receptor Antagonists with the CCK1 Receptor and P38 MAP Kinase

Cytoplasmic pH (pHi) was evaluated during Na+-glucose cotransport in Caco-2 intestinal epithelial cell monolayers. The pHi increased by 0.069 ± 0.002 within 150 s after initiation of Na+-glucose cotransport. This increase occurred in parallel with glucose uptake and required expression of the intestinal Na+-glucose cotransporter SGLT1. S-3226, a preferential inhibitor of Na+/H+ exchanger (NHE) isoform 3 (NHE3), prevented cytoplasmic alkalinization after initiation of Na+-glucose cotransport with an ED50 of 0.35 μM, consistent with inhibition of NHE3, but not NHE1 or NHE2. In contrast, HOE-694, a poor NHE3 inhibitor, failed to significantly inhibit pHi increases at <500 μM. Na+-glucose cotransport was also associated with activation of p38 mitogen-activated protein (MAP) kinase, and the p38 MAP kinase inhibitors PD-169316 and SB-202190 prevented pHi increases by 100 ± 0.1 and 86 ± 0.1%, respectively. Conversely, activation of p38 MAP kinase with anisomycin induced NHE3-dependent cytoplasmic alkalinization in the absence of Na+-glucose cotransport. These data show that NHE3-dependent cytoplasmic alkalinization occurs after initiation of SGLT1-mediated Na+-glucose cotransport and that the mechanism of this NHE3 activation requires p38 MAP kinase activity. This coordinated regulation of glucose (SGLT1) and Na+ (NHE3) absorptive processes may represent a functional activation of absorptive enterocytes by luminal nutrients.

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Incretins Enhance PGF2α-Induced Synthesis of IL-6 and Osteoprotegerin in Osteoblasts

Hormone and Metabolic Research ◽

10.1055/a-1713-7967 ◽

2022 ◽

Vol 54 (01) ◽

pp. 42-49

Author(s):

Tomoyuki Hioki ◽

Gen Kuroyanagi ◽

Kazuhiko Fujita ◽

Go Sakai ◽

Tetsu Kawabata ◽

...

Keyword(s):

Map Kinase ◽

Prostaglandin F2α ◽

P38 Map Kinase ◽

Β Cells ◽

Kinase C ◽

Protein Map ◽

Mitogen Activated Protein ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

AbstractIncretins including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which are secreted from the small intestine after oral food ingestion, are currently well-known to stimulate insulin secretion from pancreatic β-cells and used for the treatment of type 2 diabetes mellitus. We have previously reported that prostaglandin F2α (PGF2α) stimulates the synthesis of interleukin-6 (IL-6) and osteoprotegerin in osteoblast-like MC3T3-E1 cells, and that IL-6 and osteoprotegerin release are mediated through the p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways. In the present study, we investigated the effects of incretins including GLP-1 and GIP, on the PGF2α-induced synthesis of IL-6 and osteoprotegerin and examined the detailed mechanism in osteoblast-like MC3T3-E1 cells. We found that GIP and GLP-1 significantly stimulated the PGF2α-induced synthesis of IL-6 in osteoblast-like MC3T3-E1 cells. In addition, GIP and GLP-1 significantly enhanced the PGF2α-induced mRNA expression levels of IL-6. On the other hand, GIP and GLP-1 markedly stimulated the PGF2α-induced synthesis of osteoprotegerin. However, the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, or JNK induced by PGF2α was not affected by GIP or GLP-1. Therefore, these results strongly suggest that incretins enhance the PGF2α-induced synthesis of IL-6 and osteoprotegerin in osteoblast-like MC3T3-E1 cells. However, these syntheses are not mediated through p44/p42 MAP kinase, p38 MAP kinase, or JNK pathways.

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Legionella pneumophila Suppresses Macrophage Interleukin-12 Production by Activating the p42/44 Mitogen-Activated Protein Kinase Cascade

Infection and Immunity ◽

10.1128/iai.71.11.6672-6675.2003 ◽

2003 ◽

Vol 71 (11) ◽

pp. 6672-6675 ◽

Cited By ~ 9

Author(s):

Kazuto Matsunaga ◽

Hiroyuki Yamaguchi ◽

Thomas W. Klein ◽

Herman Friedman ◽

Yoshimasa Yamamoto

Keyword(s):

Map Kinase ◽

Legionella Pneumophila ◽

Kinase Inhibitors ◽

Selective Inhibition ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Interleukin 12 ◽

Map Kinase Cascade ◽

Mitogen Activated Protein ◽

Kinase Cascade

ABSTRACT A possible involvement of the mitogen-activated protein (MAP) kinase cascade in the inhibition of macrophage interleukin-12 (IL-12) production by Legionella pneumophila infection was examined. The results of MAP kinase inhibition by p42/44 and p38 MAP kinase inhibitors and of p42/44 MAP kinase activity assays indicate that L. pneumophila infection of macrophages causes a selective inhibition of lipopolysaccharide-induced IL-12 production by activating the p42/44 MAP kinase cascade. In addition, it was also revealed that the p38 MAP kinase may be important for the production of IL-12 but not for the inhibition caused by L. pneumophila infection.

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Mitogen-Activated Protein (MAP) Kinases Are Involved in Interleukin-1 (IL-1)-Induced IL-6 Synthesis in Osteoblasts: Modulation Not of p38 MAP Kinase, But of p42/p44 MAP Kinase by IL-1-Activated Protein Kinase C1

Endocrinology ◽

10.1210/endo.140.11.7123 ◽

1999 ◽

Vol 140 (11) ◽

pp. 5120-5125 ◽

Cited By ~ 20

Author(s):

Masaichi Miwa ◽

Osamu Kozawa ◽

Haruhiko Tokuda ◽

Toshihiko Uematsu

Keyword(s):

Protein Kinase ◽

Map Kinase ◽

Map Kinases ◽

Interleukin 1 ◽

P38 Map Kinase ◽

Protein Map ◽

Mitogen Activated Protein

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p38 mitogen-activated protein (MAP) kinase but not p44/p42 MAP kinase is involved in prostaglandin E1-induced vascular endothelial growth factor synthesis in osteoblasts

Journal of Endocrinology ◽

10.1677/joe.0.1700629 ◽

2001 ◽

Vol 170 (3) ◽

pp. 629-638 ◽

Cited By ~ 16

Author(s):

H Tokuda ◽

O Kozawa ◽

M Miwa ◽

T Uematsu

Keyword(s):

Map Kinase ◽

Cholera Toxin ◽

Prostaglandin E1 ◽

Specific Inhibitor ◽

P38 Map Kinase ◽

Vascular Endothelial ◽

Kinase Activation ◽

Protein Map ◽

Mitogen Activated Protein ◽

Endothelial Growth Factor

We investigated the mechanism underlying vascular endothelial growth factor (VEGF) synthesis stimulated by prostaglandin E1 (PGE1) in osteoblast-like MC3T3-E1 cells. PGE1 induced the phosphorylation of both p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase. SB203580, a specific inhibitor of p38 MAP kinase, inhibited the PGE1-stimulated VEGF synthesis as well as PGE1-induced phosphorylation of p38 MAP kinase. PD98059, an inhibitor of the upstream kinase that activates p44/p42 MAP kinase, which reduced the PGE1-induced phosphorylation of p44/p42 MAP kinase, had little effect on the VEGF synthesis stimulated by PGE1. AH-6809, an antagonist of the subtypes of the PGE receptor, EP1 and EP2, or SC-19220, an antagonist of EP1 receptor, did not inhibit the PGE1-induced VEGF synthesis. H-89, an inhibitor of cAMP-dependent protein kinase, and SQ22536, an inhibitor of adenylate cyclase, reduced the VEGF synthesis induced by PGE1. Cholera toxin, an activator of G(s), and forskolin, an activator of adenylate cyclase, induced VEGF synthesis. SB203580 and PD169316, another specific inhibitor of p38 MAP kinase, reduced the cholera toxin-, forskolin- or 8bromo-cAMP-stimulated VEGF synthesis. However, PD98059 failed to affect the VEGF synthesis stimulated by cholera toxin, forskolin or 8-bromoadenosine-3',5'-cyclic monophosphate (8bromo-cAMP). SB203580 reduced the phosphorylation of p38 MAP kinase induced by forskolin or 8bromo-cAMP. These results strongly suggest that p44/p42 MAP kinase activation is not involved in the PGE1-stimulated VEGF synthesis in osteoblasts but that p38 MAP kinase activation is involved.

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Transforming Growth Factor-β1 Impairs Endothelin-1-Mediated Contraction of Brain Vessels by Inducing Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 and Inhibiting p38 MAP Kinase

Molecular Pharmacology ◽

10.1124/mol.107.039602 ◽

2007 ◽

Vol 72 (6) ◽

pp. 1476-1483 ◽

Cited By ~ 30

Author(s):

Xin-Kang Tong ◽

Edith Hamel

Keyword(s):

Growth Factor ◽

Map Kinase ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

P38 Map Kinase ◽

Brain Vessels ◽

Endothelin 1 ◽

Map Kinase Phosphatase ◽

Protein Map ◽

Mitogen Activated Protein

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Inhibition by adenylyl cyclase-cAMP system of ET-1-induced HSP27 in osteoblasts

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.6.e1260 ◽

2001 ◽

Vol 281 (6) ◽

pp. E1260-E1266 ◽

Cited By ~ 4

Author(s):

Daijiro Hatakeyama ◽

Osamu Kozawa ◽

Masayuki Niwa ◽

Hiroyuki Matsuno ◽

Kanefusa Kato ◽

...

Keyword(s):

Map Kinase ◽

Adenylyl Cyclase ◽

Mrna Level ◽

P38 Map Kinase ◽

Hsp 27 ◽

Kinase C ◽

Protein Map ◽

Mitogen Activated Protein ◽

Camp System ◽

Kinase Phosphorylation

We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12- O-tetradecanoylphorbol-13-acetate (TPA). PGE1, an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE1. Forskolin, DBcAMP, and PGE1suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.

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Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis

Biochemical Journal ◽

10.1042/bj20020101 ◽

2002 ◽

Vol 368 (3) ◽

pp. 705-720 ◽

Cited By ~ 94

Author(s):

Koichi SAEKI ◽

Norihiko KOBAYASHI ◽

Yuko INAZAWA ◽

Hong ZHANG ◽

Hideki NISHITOH ◽

...

Keyword(s):

Cell Death ◽

Map Kinase ◽

Map Kinases ◽

Specific Inhibitor ◽

P38 Map Kinase ◽

Dominant Negative ◽

Chemically Induced ◽

Protein Map ◽

Mitogen Activated Protein ◽

Induced Apoptosis

We investigated intracellular signalling pathways for apoptosis induced by epigallocatechin-3-gallate (EGCG) as compared with those induced by a toxic chemical substance (etoposide, VP16) or the death receptor ligand [tumour necrosis factor (TNF)]. EGCG as well as VP16 and TNF induced activation of two apoptosis-regulating mitogen-activated protein (MAP) kinases, namely c-Jun N-terminal kinase (JNK) and p38 MAP kinase, in both human leukaemic U937 and OCI-AML1a cells. In U937 cells, the apoptosis and activation of caspases-3 and −9 induced by EGCG but not VP16 and TNF were inhibited with SB203580, a specific inhibitor of p38, while those induced by EGCG and VP16 but not TNF were inhibited with SB202190, a rather broad inhibitor of JNK and p38. In contrast, the EGCG-induced apoptosis in OCI-AML1a cells was resistant to SB203580 but not to SB202190. Unlike TNF, EGCG did not induce the activation of nuclear factor-κB but rather induced the primary activation of caspase-9. N-Acetyl-l-cysteine (NAC) almost completely abolished apoptosis induced by EGCG under conditions in which the apoptosis induced by VP16 or TNF was not affected. The JNK/p38 activation by EGCG was also potently inhibited by NAC, whereas those by VP16 and TNF were either not or only minimally affected by NAC. In addition, dithiothreitol also suppressed both apoptosis and JNK/p38 activation by EGCG, and EGCG-induced activation of MAP kinase kinase (MKK) 3/6, MKK4 and apoptosis-regulating kinase 1 (ASK1) was suppressed by NAC. Dominant negative ASK1, MKK6, MKK4 and JNK1 potently inhibited EGCG-induced cell death. EGCG induced an intracellular increase in reactive oxygen species and GSSG, both of which were also inhibited by NAC, and the decreased synthesis of glutathione rendered the cell susceptible to EGCG-induced apoptosis. Taken together these results strongly suggest that EGCG executed apoptotic cell death via an ASK1, MKK and JNK/p38 cascade which is triggered by NAC-sensitive intracellular oxidative events in a manner distinct from chemically induced or receptor-mediated apoptosis.

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Suppression subtractive hybridization (SSH) identifies prolactin stimulation of p38 MAP kinase gene expression in Nb2 T lymphoma cells: molecular cloning of rat p38 MAP kinase

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0200151 ◽

1998 ◽

Vol 20 (1) ◽

pp. 151-156 ◽

Cited By ~ 21

Author(s):

E Nemeth ◽

C Bole-Feysot ◽

LS Tashima

Keyword(s):

Map Kinase ◽

Suppression Subtractive Hybridization ◽

Subtractive Hybridization ◽

P38 Map Kinase ◽

Kinase Gene ◽

Nb2 Cells ◽

Protein Map ◽

T Lymphoma Cells ◽

Mitogen Activated Protein ◽

T Lymphoma

Suppression Subtractive Hybridization (SSH) has been used to compare rat Nb2 cells treated with prolactin for 1 hour with untreated cells. This new method for identifying differentially expressed genes showed that the mRNAs for at least three genes were elevated by such treatment, including a p38 mitogen activated protein (MAP) kinase. The p38 MAP kinase was cloned and the full length cDNA sequence was determined.

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