Tumor necrosis factor: Biology and therapeutic inhibitors Konstantinos A. Papadakis, Stephan R. Targan  Gastroenterology  Volume 119, Issue 4, Pages 1148-1157 (October 2000) DOI: 10.1053/gast.2000.18160 Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 1 Signal transduction by TNF through TNFR1 and TNFR2. Binding of TNF to TNFR1 leads to receptor aggregation after dissociation of SODD from its death domain. TRADD, which is now able to associate with the intracellular domain of the receptor, recruits TRAF2, RIP, and FADD to the receptor complex. The receptor complex activates IκB kinase (IKKα-IKKβ) through the PI(3)K-Akt and TRAF2-NIK signaling pathways. IκB kinase then phosphorylates IκB, which dissociates from the IκB/NF-κB complex. Released NF-κB is now able to translocate to the nucleus and induce gene transcription. TRAF2 activates JNK through MEKK1, while FADD induces apoptosis. Activation of NF-κB protects the cells from TNF-induced apoptosis and induces genes associated with inflammation. Binding of TNF to TNFR2 leads to TRAF2 recruitment to the intracellular domain of the receptor, which forms homodimers or heterodimers with TRAF1. cIAP1/2 are also recruited to the receptor complex. TRAF2 activates JNK and NF-κB. TNF binding to TNFR2 can also augment signaling through TNFR1 by a mechanism of “ligand passing.” sTNF, soluble TNF; mTNF, membrane TNF. Gastroenterology 2000 119, 1148-1157DOI: (10.1053/gast.2000.18160) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 2 A model role of TNF in the pathogenesis of mucosal inflammation. Bacterial products activate mucosal immune cells, e.g., macrophages, to secrete TNF. (1) TNF induces the production of MMPs from stromal cells that contribute to tissue injury. (2) TNF directly activates endothelial cells by up-regulating adhesion molecules. (3) It also induces the secretion of cytokines and chemokines from both endothelial cells and mucosal mononuclear cells. (4) TNF up-regulates IFN-γ production by mucosal T cells. (5) Epithelial cells secrete chemokines in response to TNF, for example IL-8, and contribute to the recruitment of inflammatory cells to the epithelium and submucosa. (6) TNF in combination with IFN-γ may lead to apoptosis of epithelial cells and disruption of the epithelial barrier, leading to a “leaky mucosa” and perpetuation of the inflammation. (7) TNF activates and mobilizes immature dendritic cells to the regional lymph nodes, (8) where they initiate an adaptive immune response. (9) The combined effects of TNF on activation and mobilization of immune cells and activation of endothelial cells lead to recruitment of monocytes and activated T cells to the intestinal mucosa leading to granuloma formation. MMPs, matrix metalloproteinases; EC, endothelial cells; V, venule; MCP-1, monocyte chemotactic protein 1; MIP-1α, macrophage inflammatory protein 1α; RANTES, regulated on activation, normal T cell expressed and secreted; LP, lamina propria; IEC, intestinal epithelial cells; PP, Peyer's patch; IDC, immature dendritic cells; MLN, mesenteric lymph node; MDC, mature dendritic cells; B, B lymphocyte; T, T lymphocyte; Mø, macrophage. Gastroenterology 2000 119, 1148-1157DOI: (10.1053/gast.2000.18160) Copyright © 2000 American Gastroenterological Association Terms and Conditions

Fig. 3 Activation pathways leading to TNF production. Each activation pathway may vary depending on the cell type, for example macrophage or T cell, and the type of extracellular stimulus. Each step in the TNF production and secretion pathway is a potential target for therapeutic manipulation using specific inhibitors (shown in circled numbers). Gastroenterology 2000 119, 1148-1157DOI: (10.1053/gast.2000.18160) Copyright © 2000 American Gastroenterological Association Terms and Conditions