Siegmund, Daniela and Ehrenschwender, Martin and Wajant, Harald (2018) TNFR2 unlocks a RIPK1 kinase activity-dependent mode of proinflammatory TNFR1 signaling. CELL DEATH & DISEASE, 9: 921. ISSN 2041-4889,
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TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1 beta. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1 beta was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1 beta was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NECROSIS-FACTOR TNF; MYCOBACTERIUM-TUBERCULOSIS; CELL-DEATH; MACROPHAGES; APOPTOSIS; ACTIVATION; ALPHA; LPS; INFLAMMATION; NECROPTOSIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Dec 2019 08:25 |
| Last Modified: | 13 Dec 2019 08:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13866 |
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