C-reactive protein increases F-actin assembly and cortical distribution with resultant loss of lamellipod formation in human neutrophils.
C-reactive protein (CRP) inhibits neutrophil movement through a p38 MAP kinase pathway. We hypothesized that CRP altered F-actin content and distribution on human neutrophils as a means of inhibiting movement. CRP produced simultaneous increased F-actin and decreased G-actin levels. CRP increased F-actin levels in a concentration-dependent manner once a threshold (>100 microg/ml) was reached, and transiently increased F-actin (peak levels at 2.5 and 10 min) that returned to baseline by 30 min. Confocal microscopy of neutrophils revealed that fMLP provoked acquisition of a migratory phenotype as evidenced by the appearance of F-actin rich lamellipods. In contrast, CRP caused neutrophil rounding, prevented lamellipod formation and shifted F-actin from the cytoskeleton to the cortex. The p38 MAP kinase inhibitor, SB203580, produced a similar effect on neutrophil shape. Concentrations of SB203580 that dramatically decreased p38 activity in neutrophils also caused round cell morphology and cortical F-actin distribution. Since CRP inhibits p38 MAP kinase and p38 blockade leads to actin polymerization and prevention of lamellipod formation, it is concluded that round morphology and loss of lamellipod formation result from CRP inhibition of p38 MAP kinase. Understanding the signal transduction of CRP prevention of lamellipod formation will aid in the development of therapeutic agents against neutrophil-associated inflammatory disease.
Yates-Siilata
Kristine E
KE
Cell and Molecular Biology Program, Saint Louis University, St. Louis, MO 63104, USA.
Dahms
Thomas E
TE
Webster
Robert O
RO
Heuertz
Rita M
RM
D000199:Actins / Q000378:metabolism*; D002097:C-Reactive Protein / Q000032:analysis / Q000502:physiology*; D048430:Cell Shape; D003600:Cytosol / Q000648:ultrastructure; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009504:Neutrophils / Q000648:ultrastructure*; D011554:Pseudopodia / Q000648:ultrastructure*; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D007093:Imidazoles; D011725:Pyridines; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580