Targeting TNF-α: A novel therapeutic approach for asthma

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Presentation transcript:

Targeting TNF-α: A novel therapeutic approach for asthma Christopher Brightling, PhD, MRCP, Mike Berry, MD, MRCP, Yassine Amrani, PhD Journal of Allergy and Clinical Immunology Volume 121, Issue 1, Pages 5-10 (January 2008) DOI: 10.1016/j.jaci.2007.10.028 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Summary of TNF-α biology and signaling. The cascade of events involved in TNF-α signaling and receptor function is shown. See text for details. TACE, TNF-α–converting enzyme; NFκB, nuclear factor κB. Journal of Allergy and Clinical Immunology 2008 121, 5-10DOI: (10.1016/j.jaci.2007.10.028) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Role of TNF-α in the pathogenesis of asthma. TNF-α plays a central role in many of the features of the asthma paradigm by exerting important effects on both inflammatory and structural cells. See text for details. Journal of Allergy and Clinical Immunology 2008 121, 5-10DOI: (10.1016/j.jaci.2007.10.028) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Molecular mechanisms activated in ASM induced by TNF-α–activated molecular mechanisms in ASM possibly contributing to AHR in asthma. TNF-α might modulate AHR through a number of possible mechanisms: (1) enhanced receptor-associated calcium signals as a result of an increased expression, function, or both of the receptor G protein (Gaq or Gai); (2) altered signal transduction, such as increased phospholipase C (PLCβ) expression, activity, or both; (3) abnormal calcium handling by exerting effects on key enzymes that regulate inositol-1,4,5-trisphosphate (IP3) metabolism, such as 5-phosphatase I and II, effects on function, and/or the expression of Ryanodine receptors (RyR), IP3 receptor (IP3R), or calcium ATPases called sarcoendoplasmic calcium ATPases (SERCA), which regulate calcium fluxes, or calmodulin (CaM); and (4) changes in calcium sensitivity mediated by effects on RhoA expression or increases in both myosin light chain kinase (MLCK) or myosin light chain phosphatase (Pase) content, activity, or both. See text for details. Journal of Allergy and Clinical Immunology 2008 121, 5-10DOI: (10.1016/j.jaci.2007.10.028) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions