Targeting TNF-α: A novel therapeutic approach for asthma

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.

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.

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.