Interferons modulate mitogen-induced protein synthesis in airway smooth muscle.
Severe asthma is characterized by increased airway smooth muscle (ASM) mass due, in part, to ASM cell growth and contractile protein expression associated with increased protein synthesis. Little is known regarding the combined effects of mitogens and interferons on ASM cytosolic protein synthesis. We demonstrate that human ASM mitogens including PDGF, EGF, and thrombin stimulate protein synthesis. Surprisingly, pleiotropic cytokines IFN-beta and IFN-gamma, which inhibit ASM proliferation, also increased cytosolic protein content in ASM cells. Thus IFN-beta alone significantly increased protein synthesis by 1.62 +/- 0.09-fold that was further enhanced by EGF to 2.52 +/- 0.17-fold. IFN-gamma alone also stimulated protein synthesis by 1.91 +/- 0.15-fold; treatment of cells with PDGF, EGF, and thrombin in the presence of IFN-gamma stimulated protein synthesis by 2.24 +/- 0.3-, 1.25 +/- 0.17-, and 2.67 +/- 0.34-fold, respectively, compared with growth factors alone. The mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) inhibition with rapamycin inhibited IFN- and EGF-induced protein synthesis, suggesting that IFN-induced protein synthesis is modulated by mTOR/S6K1 activation. Furthermore, overexpression of tumor suppressor protein tuberous sclerosis complex 2 (TSC2), which is an upstream negative regulator of mTOR/S6K1 signaling, also inhibited mitogen-induced protein synthesis in ASM cells. IFN-beta and IFN-gamma stimulated miR143/145 microRNA expression and increased SM alpha-actin accumulation but had little effect on ASM cell size. In contrast, EGF increased ASM cell size but had little effect on miR143/145 expression. Our data demonstrate that both IFNs and mitogens stimulate protein synthesis but have differential effects on cell size and contractile protein expression and suggest that combined effects of IFNs and mitogens may contribute to ASM cell growth, contractile protein expression, and ASM remodeling in asthma.
Goncharova
Elena A
EA
Pulmonary, Allergy, and Critical Care Division, Airway Biology Initiative, Department of Medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Lim
Poay N
PN
Chisolm
Amelia
A
Fogle
Homer W
HW
Taylor
Jerome H
JH
Goncharov
Dmitry A
DA
Eszterhas
Andrew
A
Panettieri
Reynold A
RA
Krymskaya
Vera P
VP
D000818:Animals; D001249:Asthma / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000033:anatomy & histology / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin / Q000494:pharmacology
D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D004815:Epidermal Growth Factor; D007372:Interferons; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin
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