Human colonic epithelial cells detect and respond to C5a via apically expressed C5aR through the ERK pathway

Am J Physiol Cell Physiol. 2012 Jun 15;302(12):C1731-40. doi: 10.1152/ajpcell.00213.2011. Epub 2012 Apr 11.


Intestinal epithelial cells (IECs) exhibit numerous adaptations to maintain barrier function as well as play sentinel roles by expressing receptors for microbial products and antimicrobial peptides. The complement system is another important innate sensing and defense mechanism of the host against bacteria and increasing evidence shows that complement plays a role in colitis. The split component C5a is a potent proinflammatory molecule, and the C5a receptor (C5aR) CD88 has been reported on multiple cell types. Here, we examined the question of whether human colonic cell lines can detect activated complement via C5aR and what signaling pathway is critical in the subsequent responses. T84, HT29, and Caco2 cell lines all possessed mRNA and protein for C5aR and the decoy receptor C5L2. Polarized cells expressed the proteins on the apical cell membrane. C5a binding to the C5aR on human IECs activates the ERK pathway, which proved critical for a subsequent upregulation of IL-8 mRNA, increased permeability of monolayers, and enhanced proliferation of the cells. The fact that human IECs are capable of detecting complement activation in the lumen via this anaphylatoxin receptor highlights the potential for IECs to detect pathogens indirectly through complement activation and be primed to amplify the host response through heightened inflammatory mediator expression to further recruit immune cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Cell Polarity
  • Cell Proliferation
  • Colon / drug effects
  • Colon / enzymology*
  • Colon / immunology
  • Complement Activation* / drug effects
  • Complement C5a / genetics
  • Complement C5a / metabolism*
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology*
  • Epithelial Cells / immunology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • HT29 Cells
  • Humans
  • Immunity, Innate
  • Immunity, Mucosal
  • Inflammation / enzymology
  • Inflammation / immunology
  • Interleukin-8 / genetics
  • Intestinal Absorption
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / immunology
  • MAP Kinase Signaling System* / drug effects
  • Permeability
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism*
  • Time Factors
  • Up-Regulation


  • C5AR1 protein, human
  • C5aR2 protein, human
  • CXCL8 protein, human
  • Interleukin-8
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Receptor, Anaphylatoxin C5a
  • Receptors, Chemokine
  • Receptors, Complement
  • Complement C5a
  • Extracellular Signal-Regulated MAP Kinases