Figure 1: Role of SpA in TNFR1 regulation. (a) SpA is recognized by TNFR1 and the signaling cascade is initiated through the adaptor proteins TRADD/RIP/TRAF2, which subsequently activate MAPK kinases (p38 and JNK 1/2) and induce translocation of transcription factors AP-1 and NF-κB into the nucleus. Activation of AP-1 and NF-κB leads to transcription of genes encoding proinflammatory cytokines and chemokines. (b) SpA through interaction with EGFR and activation of c-Src-Erk1/2 stimulates the activity of TACE (ADAM-17), which cleaves and releases TNFR1 from the airway surface. TNFR1 is then available to neutralize free SpA and TNF-α ligands. AP-1, activator protein 1; ATF-2, activating transcription factor 2; EGFR, epidermal growth factor receptor; NF-κB, nuclear factor κB; RIP, receptor-interacting protein; TACE, tumor necrosis factor-α-converting enzyme; TNFR1, tumor necrosis factor receptor 1; TRADD, tumor necrosis factor receptor- (TNFR-) associated death domain; TRAF2, tumor necrosis factor receptor-associated factor 2.