Characterization of the mechanism underlying steroid resistance in asthma.
Omar Tliba, DVM, PhD
Associate Professor, Department of Pharmaceutical Sciences
Thomas Jefferson University - Jefferson College of Pharmacy
Health Professions Academic Building
901 Walnut Street, Rm 910
Philadelphia, PA 19107-5233
My current research efforts toward understanding the mechanism underlying steroid resistance in asthma are focused in 2 major areas: 1) Use airway smooth muscle (ASM) cells as a model to gain mechanistic insight in the development of steroid insensitivity in severe asthma. While much research aimed at understanding the basis of insensitivity to glucocorticoid (GC) therapy in severe asthmatics focused on the role of immune cells, little has been done to clarify the role of ASM cells. Recent studies performed on bronchial biopsies from asthmatics treated with inhaled or oral GCs showed a persistent expression of chemokines in ASM bundles. The expression of these genes correlated with the severity of asthma. Our findings replicated this finding in vitro using cultured human ASM cells. The induction of pro-asthmatic genes is less sensitive to inhibition by GCs when such induction was triggered by TNF and IFN combination. We use ASM as a model to further define the mechanisms involved in steroid insensitivity. 2) Characterize the mechanisms that regulate GC receptor (GR) phosphorylation with a primary focus on the role of Mitogen-Activated Protein Kinase (MAPK) pathways and serine/threonine protein phosphatases (PPs). Phosphorylation of glucocorticoid receptor (GR) on various residues such as serine 203 (S203), S211, and S226 plays a key role in determining the strength and duration of GR actions. At present, uncertainty still exists about the nature of the GR phosphorylation-dependent mechanisms regulating the overall cellular responsiveness to GC and which particular GR phosphorylation profile is associated with steroid insensitive conditions. Using various molecular, biochemical, and cellular strategies, our findings characterized the role of MAPK pathways and PPs that regulate GR phosphorylation, and thus function, in airway cells with a long-term goal of providing new insight into therapies aiming at restoring steroid responsiveness in patients with severe asthma. Our studies for the first established an in vitro model of steroid resistance in airway structural cells namely ASM cells exposed to the combination of TNF and IFN. This model allowed us to demonstrate the involvement of multiple molecules in the attenuation of GC signaling such as GR, PP5, IRF1, and p38. These discoveries have made significant impact on: 1) establishing a new in vitro model of steroid resistance in airway structural cells, 2) uncovering several mechanisms underlying the promotion of steroid resistance in airway cells, 3) understanding the synergistic actions between TNF and IFN.
Associate Professor of Pharmaceutical Sciences
|EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)|||||||||
|INSTITUTION AND LOCATION|
|||MM/YY||FIELD OF STUDY|
|Agro-Veterinary Institute, Annaba, Algeria ||DVM||||06/1996||Veterinary Medicine|
|University of Rennes I, France ||Master||||06/1997||Biomedical Research|
|University of Creteil, Paris XII, France ||Master||||09/1998||Life Science|
|Pasteur Institute, Paris, France||Master||||09/1999||Immunophysiology of Infectious Diseases|
|University of Tours, France||PhD||||12/2001||Immunopathology of Parasitic Diseases|
|University of Pennsylvania, Philadelphia||Postdoctoral||||01/2002||Airway physiology and pharmacology|
Positions and Employment
1993-1994 Teaching Assistant in Parasitology, Institute of Veterinary Sciences, Annaba, Algeria
2005-2007 Research Associate, University of Pennsylvania Pulmonary, Allergy & Critical Care Division, Philadelphia
2007-2008 Research Assistant Professor, University of Pennsylvania Pulmonary, Allergy & Critical Care Division, Philadelphia
2008-2012 Assistant Professor, Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia
2012-present Associate Professor, Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia
Research Publications, peer reviewed (Total of 40):
1. Tliba O, Sibille P, Boulard C, and Chauvin A: Local hepatic immune response in rats during primary infection with Fasciola hepatica. Parasite 7(1): 9-18, Mar 2000.
2. Tliba O, Sibille P, Boulard C, and Chauvin A: Early hepatic cytokine mRNA expression in experimental rat fasciolosis. Veterinary Parasitology 103(3): 237-49, Jan 28 2002.
3. Tliba O, Chauvin A, Le Vern Y, Boulard C, and Sibille P: Evaluation of the hepatic NK cell response during the early phase of Fasciola hepatica infection in rats. Veterinary Research 33(3): 327-32, May-Jun 2002.
4. Tliba O, Moire N, Le Vern Y, Boulard C, Chauvin A, and Sibille P: Early hepatic immune response in rats infected with Fasciola hepatica. Veterinary Research 33(3): 261-70, May-Jun 2002.
5. Huang CD, Tliba O, Panettieri RA Jr, and Amrani Y: Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone. American Journal of Respiratory Cell & Molecular Biology 28(3): 330-8, Mar 2003.
6. Amrani Y, Tliba O, Choubey D, Huang CD, Krymskaya VP, Eszterhas A, Lazaar AL, and Panettieri RA Jr: IFN-gamma inhibits human airway smooth muscle cell proliferation by modulating the E2F-1/Rb pathway. American Journal of Physiology - Lung Cellular & Molecular Physiology 284(6): L1063-71, Jun 2003.
7. Chen H, Tliba O, Van Besien CR, Panettieri RA Jr, and Amrani Y: TNF-[alpha] modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl. Journal of Applied Physiology 95(2): 864-72; discussion 863, Aug 2003.
8. Tliba O, Deshpande D, Chen H., Van Besien C, Kannan M, Panettieri RA Jr, and Amrani Y: IL-13 enhances agonist-evoked calcium signals and contractile responses in airway smooth muscle. British Journal of Pharmacology 140(7): 1159-62, Dec 2003.
9. Tliba O, Tliba S, Da Huang C, Hoffman RK, DeLong P, Panettieri RA Jr, and Amrani Y: Tumor necrosis factor alpha modulates airway smooth muscle function via the autocrine action of interferon beta. Journal of Biological Chemistry 278(50): 50615-23, Dec 12 2003.
10. Kazi AS, Lotfi S, Goncharova EA, Tliba O, Amrani Y, Krymskaya VP, and Lazaar AL: Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent. American Journal of Physiology - Lung Cellular & Molecular Physiology 286(3): L539-45, Mar 2004.
11. Tliba O, Panettieri RA Jr, Tliba S, Walseth TF, and Amrani Y: Tumor necrosis factor-alpha differentially regulates the expression of proinflammatory genes in human airway smooth muscle cells by activation of interferon-beta-dependent CD38 pathway. Molecular Pharmacology 66(2): 322-9, Aug 2004.
12. Sibille P, Tliba O, and Boulard C: Early and transient cytotoxic response of peritoneal cells from Fasciola hepatica-infected rats: transient fasciolicide activity of infected-rat peritoneal cells. Veterinary Research 35(5): 573-84, Sep-Oct 2004.
13. Syed F, Panettieri RA Jr, Tliba O, Huang C, Li K, Bracht M, Amegadzie B, Griswold D., Li L, and Amrani Y: The effect of IL-13 and IL-13R130Q, a naturally occurring IL-13 polymorphism, on the gene expression of human airway smooth muscle cells. Respiratory Research 6: 9, May 2005.
14. Huang CD, Ammit AJ, Tliba O, Kuo HP, Penn RB, Panettieri RA Jr, and Amrani Y: G-protein-coupled receptor agonists differentially regulate basal or tumor necrosis factor-alpha-stimulated activation of interleukin-6 and RANTES in human airway smooth muscle cells. Journal of Biomedical Science 12(5): 763-76, Oct 2005.
15. Kim JH, Jain D, Tliba O, Yang B, Jester WF Jr, Panettieri RA Jr, Amrani Y, and Pure E: TGF-beta potentiates airway smooth muscle responsiveness to bradykinin. American Journal of Physiology - Lung Cellular & Molecular Physiology 289(4): L511-20, Oct 2005.
16. Tliba O, Cidlowski JA, and Amrani Y: CD38 expression is insensitive to steroid action in cells treated with tumor necrosis factor-alpha and interferon-gamma by a mechanism involving the up-regulation of the glucocorticoid receptor beta isoform. Molecular Pharmacology 69(2): 588-96, Feb 2006.
17. Keslacy S, Tliba O, Baidouri H, Amrani Y: Inhibition of tumor necrosis factor-alpha-inducible inflammatory genes by interferon-gamma is associated with altered nuclear factor-kappaB transactivation and enhanced histone deacetylase activity. Molecular Pharmacology 71(2): 609-18, Feb 2007.
18. Goncharova EA, Goncharov DA, Chisolm A, Spaits MS, Lim PN, Cesarone G, Khavin I, Tliba O, Amrani Y, Panettieri RA Jr, and Krymskaya VP: Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation. Molecular Pharmacology 73(3): 778-88, March 2008.
19. Tliba O, Damera G, Banerjee A, Gu Su, Baidouri H, Keslacy S, and Amrani Y: Cytokines Induce an Early Steroid Resistance in Airway Smooth Muscle Cells: Novel Role of IRF-1. American Journal of Respiratory Cell and Molecular Biology 38(4): 463-72, April 2008.
20. Banerjee A, Damera G, Bhandare R, Gu S, Sanchez Y, Panettieri R, and Tliba O: Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. British Journal of Pharmacology 2008 Sep;155(1):84-92.
21. Jain D, Keslacy S, Tliba O, Cao Y, Kierstein S, Amin K, Panettieri RA Jr, Haczku A, and Amrani Y: Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness. Immunobiology 213(6): 499-509, June 2008.
22. Bailey M, Kierstein S, Spaits M, Tliba O, Sheridan JF, Panettieri RA, and Haczku A: Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production. Journal of Immunology 2009 Jun 15;182(12):7888-96.
23. Goncharova EA, Goncharov DA, Damera G, Tliba O, Amrani Y, Panettieri RA Jr, and Krymskaya VP: Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis. Molecular Pharmacology 2009 Oct;76(4):766-77
24. Bhandare R, Damera G, Banerjee A, Flammer JR, Keslacy S, Rogatsky I, Panettieri RA, Amrani Y, and Tliba O: Glucocorticoid receptor interacting protein-1 restores glucocorticoid responsiveness in steroid-resistant airway structural cells. American Journal of Respiratory Cell and Molecular Biology 2010 Jan;42(1):9-15.
25. Damera G, Fogle HW, Lim P, Goncharova EA, Zhao H, Banerjee A, Tliba O, Krymskaya VP, and Panettieri RA Jr: Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. British Journal of Pharmacology 2009 Nov;158(6):1429-41.
26. Bouazza B, Krytska K, Debba-Pavard M, Amrani Y, Honkanen RE, Tran J, and Tliba O: Cytokines Alter Glucocorticoid Receptor Phosphorylation in Airway Cells: Role of Phosphatases. American Journal of Respiratory Cell and Molecular Biology 2012 Oct;47(4):464-73.
27. Chachi L, Shikotra A, Duffy SM, Tliba O, Brightling C, Bradding P, Amrani Y: Functional KCa3.1 Channels Regulate Steroid Insensitivity in Bronchial Smooth Muscle Cells. Journal of Immunology 2013 Sep 1;191(5):2624-36.
28. Bouazza B, Debba-Pavard M, Amrani Y, Isaacs L, O'Connell D, Ahamed S, Formella D, and Tliba O: Basal p38 MAPK Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells. American Journal of Respiratory Cell and Molecular Biology 2014 Feb;50(2):301-15.
29. Gavrila A, Chachi L, Tliba O, Brightling C, Amrani Y. The Plant Derivative Compound A Inhibits the Production of Corticosteroid-resistant Chemokines by Airway Smooth Muscle Cells. Am J Respir Cell Mol Biol. 2015 Apr 21
30. O'Connell D, Bouazza B, Amrani Y, Khatib A, Ganther JD, and Tliba O. IFNγ-induced JAK/STAT-, but not NF-κB-, signaling pathway is insensitive to glucocorticoid in airway epithelial cells. American Journal of Physiology - Lung Cellular & Molecular Physiology.2015 Jun 19.
Research Publications, peer-reviewed reviews:
31. Amrani Y, Tliba O, Deshpande DA, Walseth TF, Kannan MS, and Panettieri RA Jr: Bronchial hyperresponsiveness: insights into new signaling molecules. Current Opinion in Pharmacology 4(3): 230-4, Jun 2004.
32. Howarth PH, Knox AJ, Amrani Y, Tliba O, Panettieri RA Jr, and Johnson M: Synthetic responses in airway smooth muscle. Journal of Allergy & Clinical Immunology 114(2 Suppl): S32-50, Aug 2004.
33. Tliba O, Amrani Y, and Pannettieri RA: Is Airway Smooth Muscle the "Missing Link" Modulating Airway Inflammation in Asthma? Chest 133(1): 236-42, Jan 2008.
34. Tliba O &Amrani Y: Airway Smooth Muscle Cell as an Inflammatory Cell: Lesson Learned from IFN Signaling Pathways. Proceedings of the American Thoracic Society 1(5(1)): 106-12. Jan 2008.
35. Tliba O &Panettieri RA: Regulation of Inflammation by Airway Smooth Muscle. Current Allergy/Asthma Reports 8(3): 262-8, May 2008.
36. Tliba O &PanettieriJr RA: Noncontractile Functions of Airway Smooth Muscle Cells in Asthma. Annu Rev Physiol. Annual Review of Physiology 2009;71:509-35.
37. Damera G, Tliba O, and Panettieri RA Jr: Airway smooth muscle as an immunomodulatory cell. Pulmonary Pharmacology & Therapeutics 2009 Oct; 22(5):353-9.
38. Clarke D, Damera G, Sukkar MB, and Tliba O: Transcriptional regulation of cytokine function in airway smooth muscle cells. Pulmonary Pharmacology & Therapeutics 2009 Oct;22(5):436-45.
39. Durham A, Adcock IM, and Tliba O: Steroid resistance in severe asthma: current mechanisms and future treatment. Current Pharmaceutical Design 2011;17(7):674-84.
40. Chachi L, Gavrila A, Tliba O, Amrani Y. Abnormal corticosteroid signalling in airway smooth muscle: Mechanisms and perspectives for the treatment of severe asthma. ClinExp Allergy. 2015 May 27