C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways.

Research output: Contribution to journalArticle

Abstract

alpha 1-Antitrypsin (AAT), a major endogenous inhibitor of serine proteases, plays an important role in minimizing proteolytic injury to host tissue at sites of infection and inflammation. There is now increasing evidence that AAT undergoes post-translational modifications to yield by-products With novel biological activity. One Such molecule, the C-terminal fragment of AAT, corresponding to residues 359-394 (C-36 peptide) has been reported to stimulate significant pro-inflammatory activity in monocytes and neutrophils in vitro. In this study we showed that C-36 peptide is present in human lung tissue and mimics the effects of lipopolysaccharide (LIPS), albeit with lower magnitude, by inducing monocyte cytokine (TNF alpha, IL-I beta) and chemokine (IL-8) release in conjunction with the activation of nuclear factor-kappa B (NF-kappa B). Using receptor blocking antibodies and protein kinase inhibitors, we further demonstrated that C-36, like LPS, utilizes CD14 and Toll-like receptor 4 (TLR4) receptors and enzymes of the mitogen-activated protein kinase (MAPK) signaling pathways to stimulate monocyte TNF alpha release. The specificity of C-36 effects were demonstrated by failure of a shorter peptide (C-20) to elicit biological activity and the failure of C-36 to inhibit M/CD28-stimulated IL-2 receptor expression or proliferation in T-cells which lack TLR4 and CD14. We suggest that C-36 mediates its effects though the activation of LPS signaling pathways. (c) 2005 Elsevier Ltd. All rights reserved.

Details

Authors
  • Devipriya Subramaniyam
  • Pernilla Glader
  • Karin von Wachenfeldt
  • Jurate Burneckiene
  • Tim Stevens
  • Sabina Janciauskiene
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Clinical Medicine

Keywords

  • alpha 1-antitrypsin, C-36 peptide of alpha 1-antitrypsin, monocytes, endotoxin, lipopolysaccharide
Original languageEnglish
Pages (from-to)563-575
JournalInternational Journal of Biochemistry & Cell Biology
Volume38
Issue number4
Publication statusPublished - 2006
Publication categoryResearch
Peer-reviewedYes