C-reactive Protein Inhibits Chemotactic Peptide-induced p38 Mitogen-activated Protein Kinase Activity and Human Neutrophil Movement

Abstract

Serum levels of the acute-phase reactant, C-reactive protein (CRP), increase dramatically during acute inflammatory episodes. CRP inhibits migration of neutrophils toward the chemoattractant, f-Met-Leu-Phe (fMLP) and therefore acts as an anti-inflammatory agent. Since tyrosine kinases are involved in neutrophil migration and CRP has been shown to decrease phosphorylation of some neutrophil proteins, we hypothesized that CRP inhibits neutrophil chemotaxis via inhibition of MAP kinase activity. The importance of p38 MAP kinase in neutrophil movement was determined by use of the specific p38 MAP kinase inhibitor, SB203580. CRP and SB203580 both blocked random and fMLP-directed neutrophil movement in a concentration-dependent manner. Additionally, extracellular signal-regulated MAP kinase (ERK) was not involved in fMLP-induced neutrophil movement as determined by use of the MEKspecific inhibitor, PD98059. Blockade of ERK with PD98059 did not inhibit chemotaxis nor did it alter the ability of CRP or SB203580 to inhibit fMLP-induced chemotaxis. More importantly, CRP inhibited fMLP-induced p38 MAP kinase activity in a concentration-dependent manner as measured by an in vitro kinase assay. Impressively, CRP-mediated inhibition of p38 MAP kinase activity correlated with CRP-mediated inhibition of fMLP-induced chemotaxis (r ‫؍‬ ؊0.7144). These data show that signal transduction through p38 MAP kinase is necessary for neutrophil chemotaxis and that CRP intercedes through this pathway in inhibiting neutrophil movement.

Sensitized Mast Cells Migrate Toward the Agen: A Response Regulated by p38 Mitogen-Activated Protein Kinase and Rho-Associated Coiled-Coil-Forming Protein Kinase

“…HSP25/27 phosphorylation by MAPKAPK2/3 induces actin fiber polymerization and is required for the directional migration of many kinds of cells, including human bronchial smooth muscle and endothelial cells (24,25,(37)(38)(39)(40)(41). The p38 MAPK inhibitor, SB203580, inhibits cell migration in response to platelet-derived growth factor, sphingosine 1-phosphate, IL-1␤, and TGF-␤ (42,43). The activated mutant of MKK6, which activates p38 MAPK, increases cell migration, and either the dominant negative p38 MAPK or an HSP27 phosphorylation mutant blocks cell migration in human bronchial smooth muscle cells (37).…”

Acute Phase Proteins: Structure and Function Relationship

“…Inhibition of neutrophil chemotactic responses by CRP correlates with a reduction of chemotactic peptide-induced p38 kinase activity (Heuertz et al, 1999). In addition, CRP has been reported to induce cleavage and shedding of L-selectin from the surface of neutrophils, and markedly attenuate the attachment of human neutrophils to endothelial cells (Zouki et al, 1997).…”

C-Reactive Protein-Mediated Suppression of Nephrotoxic Nephritis: Role of Macrophages, Complement, and Fcγ Receptors

“…Transgenic mice expressing high levels of CRP and challenged by intratracheal administration of chemotactic agents also showed decreased pulmonary inflammation compared to mice expressing low levels of CRP (8,10). The mechanisms responsible for these effects are not well understood, although a direct inhibitory effect of CRP on neutrophil chemotaxis was proposed (8,11,12). CRP has also been shown to interact with PAF, and inhibition of PAF was proposed to account for its protective effect on PAF-induced shock (13).…”