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p44/p42MAPK Apoptosis JNK p38MAPK nf.kB

Fig. 2. TNF cell signaling pathway

The cytoplasmic domain of the TNF receptor I has a death domain, which has been shown to sequentially recruit TNF receptor-associated death domain (TRADD), Fas-associated death domain (FADD), and FADD-like interleukin-1ß-converting enzyme (FLICE) (also called cas-pase-8), leading to caspase-3 activation, which in turn induces apopto-sis by inducing degradation of multiple proteins (Nagata and Golstein 1995). TRADD also recruits TNF receptor-associated factor (TRAF)2, which through receptor-interacting protein (RIP) activates IKBa kinase (IKK), leading to kBa phosphorylation, ubiquitination, and degradation, which finally leads to nuclear factor-KB (NF-kB) activation. NF-kB activation is followed by the expression of various genes that can suppress the apoptosis induced by TNF. Through recruitment of TRAF2, TNF has also been shown to activate various mitogen-activated protein kinases (MAPK), including the c-jun N-terminal kinases (JNK) p38 MAPK and p42/p44 MAPK. TRAF2 is also essential for the TNF-induced activation of AKT, another cell-survival signaling pathway. Thus TNFRI activates both apoptosis and cell survival signaling pathways simultaneously.

In contrast to TNFR1, the cytoplasmic domain of TNFR2 lacks the death domain and binds TRAF1 and TRAF2 directly. Through activation of JNK, TNF activates AP-1, another redox-sensitive transcription factor. Gene-deletion studies have shown that TNFR2 can also activate NF-kB, JNK, p38 MAPK, andp42/p44 MAPK (Mukhopadhyay et al. 2001).

TNFR2 can also mediate TNF-induced apoptosis (Haridas et al. 1998). Because TNFR2 cannot recruit TRADD-FADD-FLICE, how TNFR2 mediates apoptosis is not understood. Various pieces of evidence suggest that homotrimeric TNF binds to homotrimeric TNF receptor to mediate its signals (Ameloot et al. 2001). TNF receptor deletion studies have provided evidence that this receptor communicates with receptors for other ligands, including receptor activator of NF-kB ligand (RANKL, a member of the TNF superfamily) and endotoxin (Takada and Aggarwal 2003b, 2004).

Since its discovery, TNF has been linked to a wide variety of diseases. How TNF mediates disease-causing effects is incompletely understood. The induction of pro-inflammatory genes by TNF has been linked to most diseases. The pro-inflammatory effects of TNF are primarily due to its ability to activate NF-kB. Almost all cell types, when exposed to TNF, activate NF-kB, leading to the expression of inflammatory genes. Over 200 genes have been identified that are regulated by NF-kB activation (Kumar et al. 2004). These include cyclooxygenase-2 (COX-2), lipoxygenase-2 (LOX-2), cell-adhesion molecules, inflammatory cytokines, chemokines, and inducible nitric oxide synthase (iNOS). TNF mediates some of its disease-causing effects by modulating growth. For instance, for most tumor cells TNF has been found to be a growth factor (Sugarman et al. 1985). These include ovarian cancer cells, cutaneous T cell lymphoma (Giri and Aggarwal 1998) glioblastoma (Aggarwal et al. 1996), acute myelogenous leukemia (Tucker et al. 2004), B cell lymphoma (Estrov et al. 1993), breast carcinoma (Sugarman et al. 1987), renal cell carcinoma (Chapekar et al. 1989), multiple myeloma (Borset et al. 1994), and Hodgkin's lymphoma (Hsu and Hsu 1990). Various fi-broblasts, including normal human fibroblasts, scleroderma fibroblasts, synovial fibroblasts, and periodontal fibroblasts, proliferate in response to TNF. Why on treatment with TNF some cells undergo apoptosis, others undergo proliferation, and most are unaffected is not understood. The differences are not due to lack of receptors or variations in their affinity.

10.3 Inhibitors of TNF Cell Signaling

Because of the critical role of TNF in mediating a wide variety of diseases, TNF has become an important target for drug development. Since TNF mediates its effects through activation of NF-kB, AP-1, JNK, p38 MAPK, p44/p42 MAPK, and AKT (Fig. 3); agents that can suppress these pathways have potential for therapy of TNF-linked diseases. Below is a review of inhibitors of such pathways.

10.3.1 NF-kB Blockers

Most diseases that have been linked to TNF have also been linked to NF-kB activation (Aggarwal 2003), indicating that TNF mediates its pathological effects through activation of NF-kB. Thus blockers of NF-kB have a potential for alleviating TNF-linked diseases. Several NF-kB blockers have been identified using targets that mediate the TNF-induced NF-kB activation pathway (Fig. 4). Various hormones and cytokines have also been described that can suppress TNF-induced NF-kB activation. These include IL-4, IL-13, IL-10, melanocyte-stimulating hormone (ßMSH), luteinizing hormone (LH), human chorionic gonadotrophin (HCG), and IFN-a/ß (Aggarwal et al. 2002). Other agents that suppress NF-kB activation include inhibitors of proteosomes, inhibitors of

Signaling pathways activated by TNF

Inflammatory pathway

NF-kB

Stress pathway

JNK & p38

Cell survival pathway

PI-3K/Akt

Mitogenic pathway

MAPK/Erk

JAK/STAT pathway

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