The phosphoinositide 3'-kinase p110δ modulates contractile protein production and IL-6 release in human airway smooth muscle.
Transforming growth factor (TGF) β1 increases pro-inflammatory cytokines and contractile protein expression by human airway smooth muscle (ASM) cells, which could augment airway inflammation and hyperresponsiveness. Phosphoinositide 3' kinase (PI3K) is one of the signaling pathways implicated in TGFβ1 stimulation, and may be altered in asthmatic airways. This study compared the expression of PI3K isoforms by ASM cells from donors with asthma (A), chronic obstructive pulmonary disease (COPD), or neither disease (NA), and investigated the role of PI3K isoforms in the production of TGFβ1 induced pro-inflammatory cytokine and contractile proteins in ASM cells. A cells expressed higher basal levels of p110δ mRNA compared to NA and COPD cells; however COPD cells produced more p110δ protein. TGFβ1 increased 110δ mRNA expression to the same extent in the three groups. Neither the p110δ inhibitor IC87114 (1, 10, 30 µM), the p110β inhibitor TGX221 (0.1, 1, 10 µM) nor the PI3K pan inhibitor LY294002 (3, 10 µM) had any effect on basal IL-6, calponin or smooth muscle α-actin (α-SMA) expression. However, TGFβ1 increased calponin and α-SMA expression was inhibited by IC87114 and LY294002 in all three groups. IC87114, TGX221, and LY294002 reduced TGFβ1 induced IL-6 release in a dose related manner in all groups of ASM cells. PI3K p110δ is important for TGFβ1 induced production of the contractile proteins calponin and α-SMA and the proinflammatory cytokine IL-6 in ASM cells, and may therefore be relevant as a potential therapeutic target to treat both inflammation and airway remodeling.
Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia. qi.ge@sydney.edu.au
Qi
Q
Ge
Lyn M
LM
Moir
Thomas
T
Trian
Kyoko
K
Niimi
Maree
M
Poniris
Peter R
PR
Shepherd
Judith L
JL
Black
Brian G
BG
Oliver
Janette K
JK
Burgess
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D003285:Contractile Proteins / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D014019:Tissue Donors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D002867:Chromones; D003285:Contractile Proteins; D004149:Dioxoles; C477872:IC 87114; D015850:Interleukin-6; D009025:Morpholines; D011799:Quinazolines; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D000225:Adenine