Evidence that genetic deletion of the TNF receptor p60 or p80 in macrophages modulates RANKL-induced signaling

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Abstract
In the current report, we investigated the possibility of a cross-talk between receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor α (TNF-α) using macrophage cell lines derived from wild-type mice and from mice with genetic deletion of the type 1 TNF receptor (p60-/-), the type 2 TNF receptor (p80-/-), or both receptors (p60-/-p80-/-). Deletion of TNF receptors sensitized the cells to RANKL-induced NF-κB activation, in order from least to most sensitive of p60-/- less than p80-/- less than p60-/-p80-/-. The effect on nuclear factor-κB (NF-κB) activation correlated with RANKL-induced IκBα kinase activation. Deletion of both TNF receptors also potentiated RANKL-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) activations in a dose- and time-dependent manner. Nitric oxide (NO) production and expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) induced by RANKL was also maximally induced in double knock-out cells. RANKL had no effect on the proliferation of wild-type cells, but deletion of TNF receptors induced growth modulatory effects. We also found that tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which mediates RANKL signaling, was constitutively bound to RANK in TNF receptor-deleted cells but not in wild-type cells, and this binding was enhanced by RANKL. Overall our results show that RANKL signaling is modulated by the TNF receptors and thus provide evidence of cross-talk between the receptors of 2 cytokines. (Blood. 2004;104: 4113-4121)

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