C5a differentially stimulates the ERK1/2 and p38 MAPK phosphorylation through independent signaling pathways to induced chemotactic migration in RAW264.7 macrophages

Int Immunopharmacol. 2004 Oct;4(10-11):1329-41. doi: 10.1016/j.intimp.2004.05.017.


We elucidate the roles of various protein kinases involved in complement 5a (C5a)-induced cell migration. Results showed that extracellular signal-regulated kinase1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (P13K) were necessary for C5a-induced migration, whereas protein kinase C and c-Jun N-terminal kinase (JNK) were nonessential. C5a-induced migration was also suppresses by phospholipase C (PLC) inhibitor U73122 and pertussis toxin (PTX). We found that C5a-induced, time-dependent (1) ERK1/2 phosphorylation was markedly diminished by PTX, U73122, P13K inhibitors wortmannin and LY294002 and ERK1/2 inhibitor PD98059; (2) Akt phosphorylation was also attenuated by the above inhibitors except PD98059; (3) p38 MAPK phosphorylation was only affected by PTX. Furthermore, C5a also stimulated PLCbeta(2) membrane translocation in a time-dependent manner that occurred early prior to Akt phosphorylation and could be abolished only by PTX and U73122. These results suggest that C5a, through the activation of PTX-sensitive G protein, to differentially stimulate ERK1/2 and p38 MAPK phosphorylation and evoke cell migration. That is, ERK1/2 but not p38 MAPK phosphorylation is down stream of P13K/Akt and modulated by PLC. Additionally, beta(2) isoform may be one of the participates in C5a signal and acts more upstream of P13K/Akt.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Chemotaxis*
  • Complement C5a / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Isoenzymes / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Macrophages / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phospholipase C beta
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Time Factors
  • Type C Phospholipases / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Enzyme Inhibitors
  • Isoenzymes
  • Proto-Oncogene Proteins
  • Complement C5a
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • Phospholipase C beta
  • Plcb2 protein, mouse