TSG-6 potentiates the antitissue kallikrein activity of inter-α-inhibitor through bikunin release

Rosanna Forteza*, Susana M. Casalino-Matsuda, Maria Elena Monzon, Erik Fries, Marilyn S. Rugg, Caroline M. Milner, Anthony J. Day

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


TSG-6 (the protein product of TNF-stimulated gene-6), an inflammation-associated protein, forms covalent complexes with heavy chains (HCs) from inter-α-inhibitor and pre-α-inhibitor and associates noncovalently with their common bikunin chain, potentiating the antiplasmin activity of this serine protease inhibitor. We show that TSG-6 and TSG-6·HC complexes are present in bronchoalveolar lavage fluid from patients with asthma and increase after allergen challenge. Immunodetection demonstrated elevated TSG-6 in the airway tissue and secretions of smokers. Experiments conducted in vitro with purified components revealed that bikunin·HC complexes (byproducts of TSG-6·HC formation) release bikunin. Immunoprecipitation revealed that bikunin accounts for a significant proportion of tissue kallikrein inhibition in bronchoalveolar lavage after allergen challenge but not in baseline conditions, confirming that bikunin in its free state, but not when associated with HCs, is a relevant protease inhibitor in airway secretions. In primary cultures of differentiated human airway epithelial and submucosal gland cells, TSG-6 is induced by TNF-α and IL-1β, which suggests that these cells are responsible for TSG-6 release in vivo. Bikunin and HC3 (i.e., pre-α-inhibitor) were also induced by TNF-α in primary cultures. Our results suggest that TSG-6 may play an important protective role in bronchial epithelium by increasing the antiprotease screen on the airway lumen.

Original languageEnglish (US)
Pages (from-to)20-31
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Issue number1
StatePublished - Jan 2007


  • Airway
  • Bikunin
  • IαI
  • TSG-6
  • Tissue kallikrein

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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