Activation of lymphotoxin-beta receptor enhances the LPS-induced expression of IL-8 through NF-κB and IRF-1

Lymphotoxin-beta receptor (LT beta R), a receptor for LIGHT and LT alpha(1)beta(2), is expressed on the epithelial, stromal, and myeloid cells. LT beta R is known to affect the lymphoid organ development and immune homeostasis. However, its role in macrophage function has not been sufficiently elucidated. The effect of LT beta R stimulation in the inflammatory activation of macrophages was investigated by treating the human macrophage-like cell line THP-1 with LT beta R-specific monoclonal antibody. Interestingly, combined treatment with anti-LT beta R antibody and LPS caused the synergistic induction of IL-8 expression at the transcriptional level. Analysis indicated that nuclear factor (NF)-kappa B activity was enhanced via the mitogen-activated protein kinase (MAPK) and glycogen synthase kinase (GSK)-3 beta/cAMP response element binding protein (CREB) pathways. In addition, LT beta R stimulation induced the expression of interferon regulatory factor (IRF)-1, one of the major transcription factors of IL-8 gene. Down-regulation of IRF-1 expression reduced the enhancing effect caused by LT beta R stimulation. This indicates that the LT beta R stimulation enhances the LPS-induced expression of IL-8 via the combined action of NF-kappa B and IRF-1. (C) 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.