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

Lymphotoxin-beta receptor (LTβR), a receptor for LIGHT and LTα₁β₂, is expressed on the epithelial, stromal, and myeloid cells. LTβR 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 LTβR stimulation in the inflammatory activation of macrophages was investigated by treating the human macrophage-like cell line THP-1 with LTβR-specific monoclonal antibody. Interestingly, combined treatment with anti-LTβR antibody and LPS caused the synergistic induction of IL-8 expression at the transcriptional level. Analysis indicated that nuclear factor (NF)-κB activity was enhanced via the mitogen-activated protein kinase (MAPK) and glycogen synthase kinase (GSK)-3β/cAMP response element binding protein (CREB) pathways. In addition, LTβR 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 LTβR stimulation. This indicates that the LTβR stimulation enhances the LPS-induced expression of IL-8 via the combined action of NF-κB and IRF-1.