Mechanisms of human lymphotoxin beta receptor activation on upregulation of CCL5/RANTES production

• We dissect the crosstalk between chemokine RANTES and the regulation of LTβR.
• The increase in RANTES induced by LTβR is dependent on transcriptional regulation.
• LTβR interacts with TRAF2, 3, 5 and activates MAP3Ks such as ASK1, TAK1, and MEKK1.
• JNK and ERK activation promote the binding of c-Jun and NF-κB to RANTES promoter.
• NF-κB is more important than AP-1 in the regulation of RANTES expression by LTβR.

Human lymphotoxin-β receptor (LTβR), a member of the tumor necrosis factor receptor superfamily, plays an essential role in secondary lymphoid organ development, host defense, chemokine secretion, and apoptosis. In our study, LTβR activations by different stimulations were all found to induce RANTES secretion. Overexpression of LTβR or stimulation LTβR by ligands or agonistic antibody in human lung epithelial cells induced RANTES secretion However, the regulatory mechanism and the signaling cascade have not been fully elucidated. Therefore, the aim of this study was to elucidate the mechanism underlying LTβR-mediated RANTES production. Our study indicated that activation of JNK and ERK was important for the regulation of RANTES secretion. In addition, dominant negative mutants of ASK1, TAK1, and MEKK1 inhibited LTβR-induced RANTES expression. The dominant negative mutants of TRAF2, 3, and 5 also inhibited LTβR-mediated RANTES secretion. Chromatin immunoprecipitation analysis showed that LTβR activation induced the binding of c-Jun and NF-κB to the RANTES promoter. The results of this study show that LTβR activates ASK1, TAK1, and MEKK1 cascades via TRAF2, 3, and 5, resulting in the activation of JNK and ERK, which promotes the binding of c-Jun and NF-κB to the RANTES promoter, thereby increasing RANTES expression and secretion.

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