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Inflammatory mediators modulate thrombin and cathepsin-G signaling in human bronchial fibroblasts by inducing expression of proteinase-activated receptor-4

¹Division of Cardiovascular and Respiratory Studies, Postgraduate Medical Institute of the University of Hull, Hull York Medical School, East Yorkshire, United Kingdom; and ²Surgery Unit, Castle Hill Hospital, Castle Road, Cottingham, East Yorkshire, United Kingdom

Submitted 19 June 2006 ; accepted in final form 28 November 2006

Human lung fibroblasts express proteinase-activated receptor-1 (PAR₁), PAR₂ and PAR₃, but not PAR₄. Because PAR₂ has inflammatory effects on human primary bronchial fibroblasts (HPBF), we asked 1) whether the inflammatory mediators TNF- and LPS could modify HPBF PAR expression and 2) whether modified PAR expression altered HPBF responsiveness to PAR agonists in terms of calcium signaling and cell growth. TNF- and LPS induced PAR₄ mRNA expression (RT-PCR) at 6 h and 24 h, respectively. TNF- and LPS also upregulated PAR₂ mRNA expression with similar kinetics but had negligible effect on PAR₁ and PAR₃. Flow cytometry for PAR₁, PAR₂, and PAR₃ also demonstrated selective PAR₂ upregulation in response to TNF- and LPS. Intracellular calcium signaling to SLIGKV-NH₂ (a selective PAR₂-activating peptide; PAR₂-AP) and AYPGQV-NH₂ (PAR₄-AP) revealed that TNF- and LPS induced maximal responses to these PAR agonists at 24 h and 48 h, respectively. Upregulation of PAR₂ by TNF- heightened HPBF responses to trypsin, while PAR₄ induction enabled cathepsin-G-mediated calcium signaling. Cathepsin-G also disarmed PAR₁ and PAR₂ in HPBF, while tryptase disarmed PAR₂. Induction of PAR₄ also enabled thrombin to elicit a calcium signal through both PAR₁ and PAR₄, as determined by a desensitization assay. In cell growth assays the PAR₄ agonists cathepsin-G and AYPGQV-NH₂ reduced HPBF cell number only in TNF--treated HPBF. Moreover, the mitogenic effect of thrombin (a PAR₁/PAR₄ agonist) but not the PAR₁-AP TFLLR-NH₂, was ablated in TNF--treated HPBF. These findings point to an important mechanism, whereby cellular responses to thrombin and cathepsin-G can be modified during an inflammatory response.

inflammation; fibrosis; lung; trypsin

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