The members of the tumour necrosis factor ligand family (TNFs) may induce both apoptotic and anti-apoptotic pathways. TNFs transduces cellular responses through activation of different TNF-receptors (TNFRs).

One important mechanism of cell survival is the activation of transcription of different anti-apoptotic proteins by TNFs via the nuclear factors of kappa light polypeptide in B-cells (NF-kB) signaling cascade [1].

Some TNFs/TNFRs may activate expressions of anti-apoptotic members of the Bcl-2 family. For example, expression of B-cell CLL/lymphoma 2 (Bcl-2), BCL2-like 1 (Bcl-XL) and/or BCL2-related protein A1 (BFL1) may be stimulated by:

. tumor necrosis factor, member 2 (TNF-alpha)/ tumor necrosis factor receptor superfamily, member 1A (TNF-R1) and TNF-alpha / tumor necrosis factor receptor superfamily, member 1B (TNF-R2) [2], [3];

. tumor necrosis factor (ligand) superfamily, 4 member (OX40L)/ tumor necrosis factor receptor superfamily, member 4 (OX40) [4];

. tumor necrosis factor (ligand) superfamily, member 5 (CD40L)/ tumor necrosis factor receptor superfamily, member 4 (CD40) [5];

. tumor necrosis factor (ligand) superfamily, member 11 (RANK L)/ tumor necrosis factor receptor superfamily, member 11A (RANK) [6], [7];

. tumor necrosis factor (ligand) superfamily, member 12 (TWEAK)/ tumor necrosis factor receptor superfamily, member 12A (FN14) [8];

. tumor necrosis factor (ligand) superfamily, member 13b (BAFF)/ tumor necrosis factor receptor superfamily, member 13B (TACI), tumor necrosis factor (ligand) superfamily, member 13 (APRIL)/ TACI, BAFF/ tumor necrosis factor receptor superfamily, member 17 (BCMA) and APRIL/ BCMA [9];

. nerve growth factor, beta polypeptide (NGF)/ tumor necrosis factor receptor superfamily, member 16 (NGFR) [10].

TNFRs transduces cellular responses via activation of different TNFR-associated factors (TRAFs). These are TRAF2, TRAF5 and TRAF6, mainly. TRAF3 serves as a negative regulator of the NF-kappaB pathway for many TNFRs [7], [11], [12].

Further, activation and nuclear translocation of NF-kB proteins can occur after the ligation of the cell-surface TNFRs by one of two pathways (canonical and non-canonical).

In a canonical pathways, TRAF2 activates the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKK gamma)/ inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase alpha (IKK alpha)/ inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKK beta) complex, which subsequently phosphorylates NF-kB inhibitor (I-kB). Phosphorylation of I-kB leads to it ubiquitination and degradation within the 26S proteasome. Degradation of I-kB liberates different NF-kB transfactors, allowing its rapid translocation from the cytoplasm into the nucleus where it triggers the transcription of target genes [1].

In addition, the signal from TNF-R1 may be mediated via TNFR1-associated death domain protein (TRADD)/ receptor TNFR-interacting serine-threonine kinase 1 (RIPK1) pathway [13]. The signal from NGFR may be mediated via the interleukin-1 receptor-associated kinase 1 and 2 (IRAK1/2)/ TRAF6/ sequestosome 1 (p62)/ protein kinase C, zeta (PKC-zeta) pathway [14].

In the non-canonical pathway, TRAFs stimulate NIK kinase, which subsequently activates IKK alpha by phosphorylation. IKK alpha promotes the processing of NF-kB2 from p100 to p52 form. Further processed NF-kB2 is bound to v-rel reticuloendotheliosis viral oncogene homolog B (RelB). NF-kB p52/RelB dimer is translocated into the nucleus to affect gene transcription. The non-canonical pathway is independent of IKK beta and IKK gamma [1].

In addition, the TNF-R1/ TNF-R2 signal may be mediated via NIK/ IKK/ v-rel reticuloendotheliosis viral oncogene homolog A (RelA) [3].

Then different NF-kB transfactors activate transcription of anti-apoptotic members of the Bcl-2 family (Bcl-2, Bcl-XL and BFL1), which inhibit various pro-apoptotic proteins [15], [16].

1. Orange JS, Levy O, Geha RS
   Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunological reviews 2005 Feb;203:21-37
2. Tamatani M, Che YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, Mizuno T, Tohyama M
   Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons. The Journal of biological chemistry 1999 Mar 26;274(13):8531-8
3. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB
   Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Molecular pharmacology 2006 Jan;69(1):195-206
4. Rogers PR, Song J, Gramaglia I, Killeen N, Croft M
   OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 2001 Sep;15(3):445-55
5. Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G
   NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 1999 Aug 3;96(16):9136-41
6. Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y
   TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. The Journal of experimental medicine 1997 Dec 15;186(12):2075-80
7. Hauer J, Puschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, Engelmann H
   TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs. Proceedings of the National Academy of Sciences of the United States of America 2005 Feb 22;102(8):2874-9
8. Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME
   The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. The Journal of biological chemistry 2005 Feb 4;280(5):3483-92
9. He B, Chadburn A, Jou E, Schattner EJ, Knowles DM, Cerutti A
   Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL. Journal of immunology (Baltimore, Md. : 1950) 2004 Mar 1;172(5):3268-79
10. Bui NT, Livolsi A, Peyron JF, Prehn JH
    Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha. The Journal of cell biology 2001 Feb 19;152(4):753-64
11. Takaori-Kondo A, Hori T, Fukunaga K, Morita R, Kawamata S, Uchiyama T
    Both amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-kappaB activation induced by OX40 signaling. Biochemical and biophysical research communications 2000 Jun 16;272(3):856-63
12. He L, Grammer AC, Wu X, Lipsky PE
    TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation. The Journal of biological chemistry 2004 Dec 31;279(53):55855-65
13. Baud V, Karin M
    Signal transduction by tumor necrosis factor and its relatives. Trends in cell biology 2001 Sep;11(9):372-7
14. Mamidipudi V, Li X, Wooten MW
    Identification of interleukin 1 receptor-associated kinase as a conserved component in the p75-neurotrophin receptor activation of nuclear factor-kappa B. The Journal of biological chemistry 2002 Aug 2;277(31):28010-8
15. Huang Z
    Bcl-2 family proteins as targets for anticancer drug design. Oncogene 2000 Dec 27;19(56):6627-31
16. Werner AB, de Vries E, Tait SW, Bontjer I, Borst J
    Bcl-2 family member Bfl-1/A1 sequesters truncated bid to inhibit is collaboration with pro-apoptotic Bak or Bax. The Journal of biological chemistry 2002 Jun 21;277(25):22781-8