The Glucocorticoid Dexamethasone Inhibits U937 Cell Adhesion and Neutrophil Release via RhoA/ROCK1-Dependent and Independent Pathways

Abstract

Aims: The aim of the present study was to investigate the role of the Ras homolog family member A (RhoA)/Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) signaling pathway in the inhibition of inflammatory responses by the glucocorticoid dexamethasone (Dex). Methods: The inhibitory effects of Dex and Rho-kinase inhibitor fasudil (Fas) on phorbol ester-induced release of O₂^- and MPO from neutrophils and on U937 mononuclear cell adhesion were examined along with the expression and activity levels of RhoA and ROCK1. Results: High doses of Dex rapidly inhibited the release of O₂^- and myeloperoxidase (MPO) from neutrophils and the adhesion of U937 cells, while Fas was only found to inhibit U937 cell adhesion. Additionally, Dex suppressed ROCK1 activity. However, Dex had no effects on ROCK1 or RhoA expression levels or on RhoA activity. Neither the glucocorticoid receptor antagonist mifepristone (RU-486) nor the protein synthesis inhibitor cycloheximide (CHX) was able to suppress the effects of Dex (p>0.05). Conclusions: The present findings indicate that Dex suppressed neutrophil release through ROCK1-independent mechanisms and inhibited the adhesion of U937 mononuclear cells through ROCK1-dependent non-genomic mechanisms that did not involve RhoA.

P-Hydroxycinnamaldehyde Induces B16-F1 Melanoma Cell Differentiation via the RhoA-MAPK Signaling Pathway

“…In agreement with this result, the enhanced activity of p38 MAP and the decreased activity of ERK1/2 and JNK were investigated in CMSP-treated B16-F1 cells. GTPase-RhoA and PKC are known upstream activators of cellular MAPK pathways, and [31][32][33][34]. We found that treatment of B16-F1 cells with CMSP caused decreased levels of GTPRhoA but led to no changes in p-PKC.…”

Alteration of RhoA Prenylation Ameliorates Cardiac and Vascular Remodeling in Spontaneously Hypertensive Rats

“…RhoA plays important pathophysiological roles in the cardiovascular system and in disease states such as hypertension, heart failure, stroke, diabetes and others [22,23]. We found that RhoA activation and geranylgeranylation of RhoA in the tissue of the heart increased at week 6 of SHR although there was no significant difference, but it significantly increased at week 12 of SHR (data not shown).…”

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

“…We showed that the oAβ [25][26][27][28][29][30][31][32][33][34][35] injection-induced inhibition of sAPPα and ADAM10 is associated with an activation of ROCK/PDK1 pathways. 68,75,76 ROCK activity seems to be directly upregulated by GC, 72,73,77 and ROCK/PDK1 activation after oAβ [25][26][27][28][29][30][31][32][33][34][35] is reversed by treatment with CORT113176, again constituting a vicious cycle based on feed-forward effects on GR signaling (Figure 7). 68,75,76 ROCK activity seems to be directly upregulated by GC, 72,73,77 and ROCK/PDK1 activation after oAβ [25][26][27][28][29][30][31][32][33][34][35] is reversed by treatment with CORT113176, again constituting a vicious cycle based on feed-forward effects on GR signaling …”

“…These results are consistent with several studies showing that ROCKs modulate the shedding of sAPPα through an inhibition of tumor necrosis factor-α-converting enzyme (TACE or ADAM) activity, and that ROCKs depletion reduces Aβ levels. 68,75,76 ROCK activity seems to be directly upregulated by GC, 72,73,77 and ROCK/PDK1 activation after oAβ [25][26][27][28][29][30][31][32][33][34][35] is reversed by treatment with CORT113176, again constituting a vicious cycle based on feed-forward effects on GR signaling (Figure 7). ROCK also affect Tau hyperphosphorylation.…”