Human leukocyte antigen-specific antibodies and gamma-interferon stimulate human microvascular and glomerular endothelial cells to produce complement factor C4

Rizwan Hamer, Guerman Molostvov, David Lowe, Simon Satchell, Peter Mathieson, Rebecca Ilyas, Daniel A Mitchell, For T Lam, Habib Kashi, Lam Chin Tan, Chris Imray, Simon Fletcher, David Briggs, Nithya Krishnan, Robert Higgins, Daniel Zehnder

Research output: Contribution to journalArticle (Academic Journal)peer-review

14 Citations (Scopus)

Abstract

BACKGROUND: The role of the complement system in antibody-mediated rejection has been investigated in relation to circulating complement interacting with renal microvascular endothelium, resulting in the formation of peritubular capillary C4d. However, the possible importance of local complement synthesis is less clear. The aim of this study was to determine whether human vascular endothelium could produce C4 in response to stimulation in vitro.

METHODS: Human microvascular endothelial cells and glomerular endothelial cells were stimulated with endotoxins, cytokines, and human leukocyte antigen-specific antibodies. Synthesis of complement was investigated using western blotting and indirect immunofluorescence. De novo C4 synthesis was confirmed by using C4 small interfering RNA.

RESULTS: Glomerular and microvascular endothelium, both produce C3 and C4 complement protein. Complement synthesis was stimulant-specific-C3 was produced mainly after stimulation with lipopolysaccharide whereas C4 synthesis occurred on treatment with gamma interferon. Culture with human leukocyte antigen-specific antibodies resulted in a significant increase of C4 protein synthesis by both cell lines.

CONCLUSIONS: We have shown for the first time that human microvascular endothelium can be stimulated to synthesize C4 in vitro. The implications of this for clinical transplantation, especially in the context of antibody-mediated rejection, its histological interpretation and as a potential target for therapy would have to be determined by further studies.

Original languageEnglish
Pages (from-to)867-73
Number of pages7
JournalTransplantation
Volume93
Issue number9
DOIs
Publication statusPublished - 15 May 2012

Keywords

  • Antibodies
  • Antiviral Agents
  • Blotting, Western
  • Cells, Cultured
  • Complement C4
  • Fluorescent Antibody Technique, Indirect
  • Glomerular Mesangium
  • Graft Rejection
  • HLA Antigens
  • Humans
  • Interferon-gamma
  • Kidney Transplantation

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