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Supplemental Material Supplemental Material Impact of Phosphodiesterase 4 Inhibition on the Operational Efficacy, Response Maxima and Kinetics of Indacaterol-induced Gene Expression Changes in BEAS-2B Airway Epithelial Cells: A Global Transcriptomic Analysis Radhika Joshi, Dong Yan, Omar Hamed, Mahmoud, M. Mostafa, Taruna Joshi1, Robert Newton & Mark A. Giembycz Departments of Physiology & Pharmacology (R.J., D.Y., O.H., T.J., M.A.G.) and Cell Biology & Anatomy (M.M.M., R.N.), Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 1Current affiliation: Global Development Operations, Novartis Healthcare Pvt. Ltd. Salarpuria-Sattva Knowledge City, Raidurg, Hyderabad - 500 032, India. 42 nH Salmeterol (100nM) y t i 36 Formoterol: 1.83 v i t Salmeterol: 1.84 c 30 A Indacaterol: 1.75 r e t ) r 24 d l o Indacaterol o p f Formoterol e ( 18 Salmeterol (10nM) R p[A] 45 p[A]36 E R 12 C p[A]14 Indacaterol 6 6 p[A]32 N = 7 0 -12 -11 -10 -9 -8 -7 log [LABA (M)] Supplemental Fig. 1. Effect of LABAs on the expression of luciferase activity in 6CRE BEAS- 2B reporter cells. E/[A] curves were constructed to formoterol (black circles), indacaterol (white circles) and salmeterol (grey circles). The results shown in figures 1 to 5 were obtained with a maximally-effective concentration of indacaterol (10nM, blue circle). The results shown in figures 6, 7 and 8 were obtained with submaximal concentrations (green circles) of formoterol (30pM; p[A]45), indacaterol (1nM; p[A]32) and salmeterol (0.3nM; p[A]14 and 0.5nM; p[A]36]) as indicated. In the RNA-seq experiment presented in figures 7 and 8, salmeterol (100nM, purple circle) was used to define maximal gene expression. Data points represent the mean ± s.e. mean of N independent determinations. The horizontal dashed line represents baseline luciferase activity. N.B. All LABA E/[A] curves were steep with Hill coefficients (nH) significantly greater than unity slope. Supplemental Fig. 2. Volcano plots depicting GSK 256066-induced gene expression changes in BEAS-2B cells. cDNA from GSK 256066 (10nM)-treated cells was subjected to microarray and the relative expression patterning of probe sets at 1, 2, 6 and 18h was visualized by generating volcano plots (A to D respectively). Each probe set is represented by a circle coloured grey (transcript changes from >0.67-fold to <1.5-fold), red or blue (corresponding to transcripts that are either induced or repressed by >1.5-fold and <0.67-fold respectively). The letters in circles coloured yellow correspond to a HGNC gene symbol and Affymetrix probe set ID number (shown on the right side of the figure). The horizontal and vertical dashed lines in each panel indicate the ANOVA P-value set to a value of 0.05 and baseline gene expression respectively. A. BMP2 B. C5AR1 C. CCL20 D. CD200 2 2 4 2 205289_at ) 220088_at 205476_at 209582_s_at d l ) o f N = 4 N = 4 N = 4 N = 4 ( y n a o 1 2 i r r s s A e ; r 1 p x R E 1/2 1 C e P n ( e G 1/4 1/2 1/2 1 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 E. CRISPLD2 F. DMBT1 G. DUSP1 H. FGFR2 2 2 2 4 221541_at 201044_x_at 203638_s_at ) 208250_s_at d l ) o f N = 4 N = 4 N = 4 N = 4 ( y n a o 2 i r r s s A e ; r 1 p x R E 1 C e P n ( e G 1 1/2 1 1/2 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 I. GAS1 J. IL6 K. NR4A2 L. NR4A3 4 8 16 16 204456_s_at 216248_s_at 209959_at ) 205207_at d l ) o f N = 4 N = 4 N = 4 N = 4 ( 4 8 8 y n a o r i r s A s ; e r 2 2 4 4 p x R E C e P n 2 ( 1 2 e G 1 1/2 1 1 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 M. PDE4D N. PDK4 O. PRDM1 4 4 4 228962_at 225207_at 228964_at ) d l ) o f N = 4 N = 4 N = 4 ( y n a o 2 i r r s s A e ; r 2 2 p x R E 1 C e P n ( e G 1 1 1/2 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 P. RGS2 Q. SGK1 R. SOCS3 2 4 4 202388_at 201739_at ) 206359_at d l ) o f N = 4 N = 4 N = 4 ( y n a o 2 i r r s s A e ; r 1 2 p x R E 1 C e P n ( e G 1/2 1 1/2 0 1 2 6 18 0 1 2 6 18 0 1 2 6 18 Time (h) Time (h) Time (h) Supplemental Fig. 3. Validation of GSK 256066-induced gene expression changes. cDNA was prepared from BEAS-2B cells treated for 1, 2, 6 and 18h with GSK 256066 (10nM) or vehicle and subjected to gene expression profiling by microarray. Panels show the kinetics of 18 up-regulated genes (ordered alphabetically) plotted as fold on a log2 scale where a value of 1 indicates baseline expression (dashed horizontal lines). The open circles represent data taken directly from the microarray using the probe set that gave the most robust response relative to vehicle-treated, time-matched controls. These data were validated by PCR using the same cDNA, normalised to GAPDH and expressed as fold (filled black circles). Probe set IDs and their corresponding HGNC gene symbols are indicated in each panel. The letter preceding each gene symbol and in the circles coloured yellow in figure 1 and supplemental figure 2 refer to the same gene. PCR data are the mean ± s.e. mean of N determinations. 1h 2h 1h 2h 1h 2h 1h 2h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d K V K K V K K V f d f V f d f V f f V f f S nd S S n S S rm S S rm S o n o o n o o rm o o rm o I G I G G o G G o G R I R R I R R o R R o R G +G + F + F + d+ d+ F + F + d d m m In In rm rm In In or or o o F F F F Supplemental Fig. 4. Effect of PDE4 inhibition on gene expression changes produced by submaximal concentrations of indacaterol and formoterol. BEAS-2B cells were pre-treated (30min) with either GSK 256066 (GSK; 10nM) or roflumilast (Rof; 1M) and then exposed to either indacaterol (Ind; 1nM) or formoterol (Form; 30pM) for an additional 1 and 2h. RNA was extracted, cDNA prepared and the expression of nine indacaterol-induced genes was determined by real-time PCR, normalised to GAPDH and presented as Box and Whisker plots. Data are the mean s.e. mean of N independent determinations. Statistical analysis was by repeated measures one-way ANOVA followed, when appropriate, by Tukey's multiple comparisons test.
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