Thy1 up-regulates FasL expression in lung myofibroblasts via Src family kinases.
We have previously demonstrated that myofibroblasts from lungs with bleomycin-induced fibrosis overexpress FasL molecules. Two subpopulations of fibroblasts, distinguished by their expression of Thy1 molecules, have been shown in the lungs of both mice and humans. Thy1-mediated FasL induction has been reported in T cells through the use of anti-Thy1 (G7). We therefore sought to determine whether FasL expression in lung myofibroblasts is associated with and/or dependent on Thy1 expression, and to examine the underlying mechanism of regulation. We show that myofibroblast Thy1 expression is associated with increased FasL expression. Moreover, we directly show that Thy1 activation induces FasL up-regulation. Initially, Thy1 activation causes translocation of FasL to the membrane surface, and later induces de novo synthesis of FasL at the mRNA and protein levels. In contrast to Thy1 activation, TNF-alpha and IFN-gamma do not induce FasL myofibroblast up-regulation. Using Src family kinase (SFKs) inhibitor (PP2), we show the general involvement of SFKs in Thy1 signal transduction leading to FasL up-regulation; and, using specific siRNA, we show the particular involvement of Fyn, one protein in the SFK family. These results demonstrate that Thy1 in myofibroblasts is not just a marker, but is a functional protein that transmits signals into the cell, up-regulating its FasL expression.
Cohen
Pazit Y
PY
Head, Institute for Pulmonary Medicine, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem, Israel.
Breuer
Raphael
R
Wallach-Dayan
Shulamit B
SB
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000096:biosynthesis*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018800:Thy-1 Antigens / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
C412373:AG 1879; D000998:Antiviral Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018800:Thy-1 Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn