P38 Mitogen Activated Protein Kinase Regulates Endothelial VCAM-1 Expression at the Post-transcriptional Level

Pietersma, Anneke; Tilly, Ben C.; Gaestel, Matthias; Jong, N. de; Lee, J C; Koster, J.F.; Sluiter, Wim J.

doi:10.1006/bbrc.1996.5886

Cited by 189 publications

(129 citation statements)

References 21 publications

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“…Moreover, the elevation of VCAM-1 expression only at mRNA level also suggests a potential for synergism. The discrepancy between mRNA and protein levels of VCAM-1 is not unknown [44,45]. MicroRNAs may block translation of VCAM-1 without degradation of mRNA or post-translational degradation can decrease the protein level, however, the exploration of the molecular mechanism is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 93%

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

Jani

Schwaner

Kajdácsi

et al. 2016

Molecular Immunology

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Abbreviation: HUVEC, human umbilical vein endothelial cell; MBL, mannan-binding lectin; MASP, mannan-binding lectin-associated serine protease; PAR, protease-activated receptor. AbstractThe complement system and neutrophil granulocytes are indispensable in the immune response against extracellular pathogens such as bacteria and fungi. Endothelial cells also participate in antimicrobial immunity largely by regulating the homing of leukocytes through their cytokine production and their pattern of cell surface adhesion molecules. We have previously shown that mannan-binding lectin-associated serine protease-1 (MASP-1), a complement lectin pathway enzyme, is able to activate endothelial cells by cleaving protease activated receptors, which leads to cytokine production and enables neutrophil chemotaxis. Therefore, we aimed to investigate how recombinant MASP-1 (rMASP-1) can modify the pattern of P-selectin, E-selectin, ICAM-1, ICAM-2, and VCAM-1 adhesion molecules in human umbilical vein endothelial cells (HUVEC), and whether these changes can enhance the adherence between endothelial cells and neutrophil granulocyte model cells (differentiated PLB-985). We found that HUVECs activated by rMASP-1 decreased the expression of ICAM-2 and increased that of E-selectin, whereas ICAM-1, VCAM-1 and P-selectin expression remained unchanged. Furthermore, these changes resulted in increased adherence between differentiated PLB-985 cells and endothelial cells. Our finding suggests that complement MASP-1 can increase adhesion between neutrophils and endothelial cells in a direct fashion. This is in agreement with our previous finding that MASP-1 increases the production of pro-inflammatory cytokines (such as IL-6 and IL-8) and chemotaxis, and may thereby boost neutrophil functions. This newly described cooperation between complement lectin pathway and neutrophils via endothelial cells may be an effective tool to enhance the antimicrobial immune response.

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Section: Discussionmentioning

confidence: 93%

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

Jani

Schwaner

Kajdácsi

et al. 2016

Molecular Immunology

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“…Rheumatoid arthritis, Alzheimer's disease and inflammatory bowel disease are all postulated to be regulated in part by the p38 pathway [87][88][89]. The activation of the p38 pathway plays essential roles in the production of proinflammatory cytokines (IL-1β, TNF-α and IL-6) [90]; induction of enzymes such as COX-2 which controls connective tissue remodeling in pathological conditions [91]; expression of intracellular enzymes such as iNOS, a regulator of oxidation [92,93]; induction of VCAM-1 and other adherent proteins along with other inflammatory related molecules [18]. In addition, a regulatory role for p38 in the proliferation and differentiation of immune system cells such as GM-CSF, EPO, CSF and CD-40 has been established [16,94].…”

Section: Biological Consequences Of P38 Acti-vation P38 and Inflammationmentioning

confidence: 99%

Activation and signaling of the p38 MAP kinase pathway

2005

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The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

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“…ICMT Inhibition Suppresses the TNF␣ Phosphorylation of p38 MAP Kinase-p38 MAP kinase requires Rac1 for its activation by TNF␣ and has also been implicated in the regulation of expression of vascular cell adhesion molecule-1 in EC (33). To determine whether ICMT plays a role in regulating the signaling pathways downstream of Rac1, we investigated the effect of AFC on p38 MAP kinase activation by Western analysis.…”

Section: Tnf␣ Stimulation Of Ec Increases the Membrane-associatedmentioning

confidence: 99%

Tumor Necrosis Factor α Stimulation of Rac1 Activity

Papaharalambus

Sajjad

Syed

et al. 2005

Journal of Biological Chemistry

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We have previously demonstrated that both isoprenylcysteine carboxylmethyltransferase (ICMT) and one of its substrates, the RhoGTPase Rac1, are critical for the tumor necrosis factor ␣ (TNF␣) stimulation of vascular cell adhesion molecule-1 expression in endothelial cells (EC). Here, we have shown that ICMT regulates TNF␣ stimulation of Rac1 activity. TNF␣ stimulation of EC increased the membrane association of Rac1, an event that is essential for Rac1 activity. ICMT inhibitor Nacetyl-S-farnesyl-L-cysteine (AFC) blocked the accumulation of Rac1 into the membrane both in resting and TNF␣-stimulated conditions. Similarly, the membraneassociated Rac1 was lower in Icmt-deficient versus wildtype mouse embryonic fibroblasts (MEFs). TNF␣ also increased the level of GTP-Rac1, the active form of Rac1, in EC. AFC completely suppressed the TNF␣ stimulation of increase in GTP-Rac1 levels. Confocal microscopy revealed resting EC Rac1 was present in the plasma membrane and also in the perinuclear region. AFC mislocalized Rac1, both from the plasma membrane and the perinuclear region. Mislocalization of Rac1 was also observed in Icmt-deficient versus wild-type MEFs. To determine the consequences of ICMT inhibition, we investigated the effect of AFC on p38 mitogen-activated protein (MAP) kinase phosphorylation, which is downstream of Rac1. AFC inhibited the TNF␣ stimulation of p38 MAP kinase phosphorylation in EC. TNF␣ stimulation of p38 MAP kinase phosphorylation was also significantly attenuated in Icmt-deficient versus wild-type MEFs. To understand the mechanism of inhibition of Rac1 activity, we examined the effect of ICMT inhibition on the interaction of Rac1 with its inhibitor, Rho guanine nucleotide dissociation inhibitor (RhoGDI). The association of Rac1 with its inhibitor RhoGDI was dramatically increased in the Icmt-deficient versus wild-type MEFs both in resting as well as in TNF␣-stimulated conditions, suggesting that RhoGDI was involved in inhibiting Rac1 activity under the conditions of ICMT inhibition. These results suggest that ICMT regulates Rac1 activity by controlling the interaction of Rac1 with RhoGDI. We hypothesize that ICMT regulates the release of Rac1 from RhoGDI.Some signaling proteins, such as small GTPases and the ␥ subunits of heterotrimeric G proteins, end with a CAAX (C for cysteine, A for aliphatic amino acids, and X for almost any other amino acid) sequence, which is post-translationally modified in three ways (1). Isoprenylation (farnesylation or geranylgeranylation) at cysteine is followed by cleavage of the last three amino acids (AAX) (1-3). Finally, the isoprenylated cysteine is carboxyl methylated by an endoplasmic reticulum resident enzyme (4, 5) isoprenylcysteine carboxylmethyltransferase (ICMT) 1 (5). This carboxyl methylation provides additional hydrophobicity to the isoprenylated proteins. Carboxyl methylation is dependent on the first two modifications and is potentially reversible.We demonstrated that ICMT and one of its substrates, the RhoGTPase Rac1, regulate in endothelial cells...

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P38 Mitogen Activated Protein Kinase Regulates Endothelial VCAM-1 Expression at the Post-transcriptional Level

Cited by 189 publications

References 21 publications

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

Complement MASP-1 enhances adhesion between endothelial cells and neutrophils by up-regulating E‐selectin expression

Activation and signaling of the p38 MAP kinase pathway

Tumor Necrosis Factor α Stimulation of Rac1 Activity

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