TY  - JOUR
A1  - Kreckel, Jennifer
A1  - Anany, Mohammed A.
A1  - Siegmund, Daniela
A1  - Wajant, Harald
T1  - TRAF2 controls death receptor-induced caspase-8 processing and facilitates proinflammatory signaling
JF  - Frontiers in Immunology
N2  - Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) knockout (KO) cells were generated to investigate the role of TRAF2 in signaling by TNFR1 and the CD95-type death receptors (DRs) TRAILR1/2 and CD95. To prevent negative selection effects arising from the increased cell death sensitivity of TRAF2-deficient cells, cell lines were used for the generation of the TRAF2 KO variants that were protected from DR-induced apoptosis downstream of caspase-8 activation. As already described in the literature, TRAF2 KO cells displayed enhanced constitutive alternative NFκB signaling and reduced TNFR1-induced activation of the classical NFκB pathway. There was furthermore a significant but only partial reduction in CD95-type DR-induced upregulation of the proinflammatory NFκB-regulated cytokine interleukin-8 (IL8), which could be reversed by reexpression of TRAF2. In contrast, expression of the TRAF2-related TRAF1 protein failed to functionally restore TRAF2 deficiency. TRAF2 deficiency resulted furthermore in enhanced procaspase-8 processing by DRs, but this surprisingly came along with a reduction in net caspase-8 activity. In sum, our data argue for (i) a non-obligate promoting function of TRAF2 in proinflammatory DR signaling and (ii) a yet unrecognized stabilizing effect of TRAF2 on caspase-8 activity.
KW  - caspase-8
KW  - death receptors
KW  - CD95
KW  - TNFR1
KW  - TRAF1
KW  - TRAF2
KW  - TRAILR1
KW  - TRAILR2
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201822
VL  - 10
IS  - 2024
ER  - 
TY  - JOUR
A1  - Grimmig, Tanja
A1  - Moench, Romana
A1  - Kreckel, Jennifer
A1  - Haack, Stephanie
A1  - Rueckert, Felix
A1  - Rehder, Roberta
A1  - Tripathi, Sudipta
A1  - Ribas, Carmen
A1  - Chandraker, Anil
A1  - Germer, Christoph T.
A1  - Gasser, Martin
A1  - Waaga-Gasser, Ana Maria
T1  - Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer
JF  - International Journal of Molecular Sciences
N2  - Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.
KW  - tumor growth
KW  - TLR2
KW  - TLR4
KW  - TLR9
KW  - pancreatic cancer
KW  - inflammation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165743
VL  - 17
IS  - 12
ER  -