p38 MAPK is a critical regulator of the constitutive and the β4 integrin‐regulated expression of IL‐6 in human normal thymic epithelial cells

Mainiero, Fabrizio; Colombara, Michaela; Antonini, V.; Strippoli, Raffaele; Merola, Marcello; Poffe, Ornella; Tridente, Giuseppe; Ramarli, Dunia

doi:10.1002/eji.200323931

Cited by 33 publications

(34 citation statements)

References 42 publications

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“…Furthermore, as seen in Fig. 6C, in IMCE (Apc Min/+ ) cells, p38 inhibition led to a greater reduction in the leptin-induced cell proliferation than NF-nB inhibition, and this may be due to the fact that enzymatic inhibitors of p38 block both p38 phosphorylation and p38 activation-induced NF-nB activation seen in thymic epithelial cells (29).…”

Section: Discussionmentioning

confidence: 80%

Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines

Fenton

Hord

Lavigne

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The obese state is associated with elevated circulating levels of insulin, insulin-like growth factors (IGF), and leptin. Research is contradictory regarding the role of these elevated growth factors in colon cancer risk. We hypothesized that colonic epithelial cells that were Apc deficient (Apc Min/+ ) but not those expressing wild-type Apc (Apc +/+ ) would experience a hyperproliferative and antiapoptotic phenotype when exposed to these growth factors. This hypothesis was addressed using two nontumorigenic murine colonic epithelial cell lines with distinct Apc genotypes: Apc +/+ YAMC cells and Apc Min/+ IMCE cells. Cells were treated for 48 hours with various concentrations of leptin (0.001-50 ng/mL), IGF-1 (0.1-200 ng/mL), or IGF-2 (0.1-600 ng/mL). In YAMC cells, leptin caused a significant decrease in cell proliferation (P < 0.01) compared with controls due to induction of caspase activity and apoptosis. In contrast, in the IMCE cells, leptin induced a 75% increase in cell proliferation compared with controls (P < 0.0001). IGF-1 and IGF-2 also induced 50% greater proliferation in the IMCE cells (P < 0.001) compared with controls. Cotreatment of IMCE cells with leptin and either IGF-1 or IGF-2 induced greater proliferation than either growth factor alone (P < 0.0001). IMCE cell proliferation caused by leptin only treatment was associated with activation of p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and nuclear factor-KB nuclear translocation but not with MAPK kinase or Janus-activated kinase/ signal transducers and activators of transcription activation. These data provide the first evidence that leptin may interact with IGFs to promote survival and expansion of colonic epithelial cells that were Apc deficient (Apc Min/+ ) but not those expressing wild-type Apc (Apc +/+ ). (Cancer Epidemiol Biomarkers Prev 2005;14(7):1646 -52)

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Section: Discussionmentioning

confidence: 80%

Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines

Fenton

Hord

Lavigne

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…These data are consistent with the notion that H. pylori infections result in the stimulation of transcription factors which differentially affect different promoter regions. We found that the NF-IL-6 site binds H. pylori-inducible proteins belonging to the C/EBP family of transcription factors, which are involved in the regulation of immune functions and tumorigenesis and are regulated through the MAPK and NF-B pathways (18,22,29). In fact, inhibitor experiments showed that the binding complexes of NF-IL-6 were inhibited by the p38 inhibitor and the NF-B inhibitor.…”

Section: Discussionmentioning

confidence: 97%

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

Kudo

Lü

et al. 2005

Infect Immun

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RANTES, a CC chemokine, plays an important role in the inflammatory response associated with Helicobacter pylori infection. However, the mechanism by which H. pylori induces RANTES expression in the gastric mucosa is unknown. We cocultured gastric epithelial cells with wild-type H. pylori, isogenic oipA mutants, cag pathogenicity island (PAI) mutants, or double knockout mutants. Reverse transcriptase PCR showed that RANTES mRNA was induced by H. pylori and that the expression was both OipA and cag PAI dependent. Luciferase reporter gene assays and electrophoretic mobility shift assays showed that maximal H. pyloriinduced RANTES gene transcription required the presence of the interferon-stimulated responsive element (ISRE), the cyclic AMP-responsive element (CRE), nuclear factor-interleukin 6 (NF-IL-6), and two NF-B sites. OipA-and cag PAI-dependent pathways included NF-B3NF-B/NF-IL-6/ISRE pathways, and cag PAI-dependent pathways additionally included Jun N-terminal kinase3CRE/NF-B pathways. The OipAdependent pathways additionally included p383CRE/ISRE pathways. We confirmed the in vitro effects in vivo by examining RANTES mRNA levels in biopsy specimens from human gastric antral mucosa. RANTES mRNA levels in the antral mucosa were significantly higher for patients infected with cag PAI/OipA-positive H. pylori than for those infected with cag PAI/OipA-negative H. pylori or uninfected patients. The mucosal inflammatory response to H. pylori infection involves different signaling pathways for activation of the RANTES promoter, with both OipA and the cag PAI being required for full activation of the RANTES promoter. Gastric epithelial damage inHelicobacter pylori infection is thought to be related to the cellular and humoral inflammatory response to the infection. The cellular immune response to the organism initially consists of the recruitment of neutrophils, followed by T and B lymphocytes, plasma cells, and macrophages. Members of the chemokine supergene family, particularly the CXC and CC chemokine subfamilies, are thought to be responsible for recruitment of these inflammatory cells into the gastric mucosa (7,8,14,28,31,(35)(36)(37). RANTES (regulated on activation normal T cell expressed and secreted) is a CC chemokine produced by epithelial cells, CD8 ϩ T cells, fibroblasts, and platelets that mediates the trafficking and homing of classical lymphoid cells such as T cells and monocytes. RANTES also acts on a range of other cells, including basophils, eosinophils, natural killer cells, dendritic cells, and mast cells (2, 30).Increased RANTES production is a feature of H. pyloriinduced gastric inflammation (7,14,28,31,37). RANTES mRNA expression is also thought to play an important role in maintaining residual memory T lymphocytes and eosinophils in gastric mucosa following H. pylori eradication (14). The mechanisms responsible for inducible RANTES gene transcription associated with H. pylori infections have not been fully elucidated. Mori et al. (23) recently reported that the regulation of RANTES gene trans...

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“…Importantly, these in vitro functional assays recapitulate the invasion, sprouting, migration, and lumenforming steps that occur in vivo, during angiogenesis. 3,7 Laminin-binding integrins can activate PI3K-Akt, 54,55 Rac1, 56-58 Cdc42, 57,59 ERK, 12,60 p38 MAPK, 61 FAK, 60 src, 62 and Raf 63 pathways. However, only a subset of these signaling molecules (Akt, Rac1, and Cdc42) showed markedly reduced laminin-dependent activation in Cd151-null MLECs.…”

Section: Org Frommentioning

confidence: 99%

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

Takeda

Kazarov

Butterfield

et al. 2006

Blood

155

235

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Tetraspanin protein CD151 is abundant on endothelial cells. To determine whether CD151 affects angiogenesis, Cd151-null mice were prepared. Cd151-null mice showed no vascular defects during normal development or during neonatal oxygeninduced retinopathy. However, Cd151-null mice showed impaired pathologic angiogenesis in other in vivo assays (Matrigel plug, corneal micropocket, tumor implantation) and in the ex vivo aortic ring assay. Cd151-null mouse lung endothelial cells (MLECs) showed normal adhesion and proliferation, but marked alterations in vitro, in assays relevant to angiogenesis (migration, spreading, invasion, Matrigel contraction, tube and cable formation, spheroid sprouting). Consistent with these functional impairments, and with the close, preferential association of CD151 with laminin-binding integrins, Cd151-null MLECs also showed selective signaling defects, particularly on laminin substrate. Adhesion-dependent activation of PKB/c-Akt, e-NOS, Rac, and Cdc42 was diminished, but Raf, ERK, p38 MAP kinase, FAK, and Src were unaltered. In Cd151-null MLECs, connections were disrupted between laminin-binding integrins and at least 5 other proteins. In conclusion, CD151 modulates molecular organization of laminin-binding integrins, thereby supporting secondary (ie, after cell adhesion) functions of endothelial cells, which are needed for some types of pathologic angiogenesis in vivo. Selective effects of CD151 on pathologic angiogenesis make it a potentially useful target for anticancer therapy. IntroductionAngiogenesis, the formation of new blood vessels from preexisting vasculature, is crucial for many physiologic and pathologic situations. [1][2][3] It involves coordinated endothelial cell proliferation, migration, and tube formation, with integrin-type adhesion receptors playing major roles. [4][5][6] Although vitronectin-, fibronectin-, and collagen-binding integrins have been most extensively studied, laminin-binding integrins (␣3␤1, ␣6␤1, ␣6␤4) are also involved. [7][8][9][10][11] For example, during the later stages of angiogenesis, ␣3␤1 and ␣6␤1 integrins may retard morphogenic and proliferative events, while promoting basement membrane assembly, pericyte association, and tube stabilization. 7 By contrast, ␣6␤4 may regulate the onset of pathologic angiogenesis in mature blood vessels. 12 CD151, a tetraspanin protein family member, 13 associates closely with laminin-binding integrins, thereby modulating ␣3␤1-, ␣6␤1-, and ␣6␤4-dependent neurite outgrowth, cell migration, cell morphology, and adhesion strengthening. Mutation of CD151 in humans yielded kidney and skin disorders, but no obvious impairments in blood vessel formation or function were noted. 14 Mice in which Cd151 was deleted were surprisingly normal, while showing only ex vivo deficiencies in platelet aggregation, keratinocyte migration, and T-cell proliferation. 15,16 Again, there were no obvious blood vessel deficiencies. CD151 is present on many cell types, including endothelial cells, where it may either promote 17 or inhibit 18...

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p38 MAPK is a critical regulator of the constitutive and the β4 integrin‐regulated expression of IL‐6 in human normal thymic epithelial cells

Cited by 33 publications

References 42 publications

Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines

Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

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