Lymphotoxin-beta receptor signalling regulates cytokine expression via TRIM30α in a TRAF3-dependent manner

Our earlier studies indicated that activation of the lymphotoxin beta receptor (LTβR) by T cell derived LTα(1)β(2) regulates inflammatory cytokine expression. While characterizing the cellular and molecular mechanisms responsible for the down regulation of the inflammatory reaction after LTβR stimulation we were able to identify the specific induction of TRIM30α expression as a result of LTβR signalling in mouse macrophages. Furthermore, we could demonstrate that LTβR activation in these cells results in the down regulation of pro-inflammatory cytokine (e.g. TNF and IL-6) and mediator expression upon TLR4 and TLR9 re-stimulation, demonstrating that LTβR activation on mouse macrophages dampens pro-inflammatory cytokine and mediator expression. Thus, LTβR signalling renders macrophages hypo-responsive to subsequent stimulation with TLR ligands. The observation of an LTβR-mediated TLR-tolerance in the human monocyte cell line THP-1 suggests that similar signalling mechanisms seem to exist in human cells. Signalling pathway analysis clearly demonstrated that LTβR-induced TRIM30α expression is mediated by an IκBα-dependent signalling pathway. Furthermore, the LTβR-induced TRIM30α expression seems to be TRAF3 dependent. Our data suggest that LTβR activation on mouse macrophages is involved in the control of pro-inflammatory cytokine and mediator expression by activation of a signalling pathway that controls exacerbating inflammatory cytokine production.