Alternatively Spliced Forms of Tollip Regulate Inflammatory Signalling in Macrophages

Lo, Yu-Lan (Sandra), University, My, Christine Wells
Alternative splicing is one of the mechanisms which drives diversification of innate immune responses. Spliced isoforms of Toll-interacting protein (Tollip), a negative regulator of TLR2-, TLR4- and IL-1R-induced signalling, have been identified to express at endogenous level in human and mouse macrophages. In the current study, we focused on two Tollip isoforms, the full-length Tollip.a and a mouse-specific isoform Tollip.b that lacks the ubiquitin-binding CUE domain. We asked for the effects
more » ... nd consequences of alternative splicing of Tollip in innate immune responses. We wanted to know if alternative splicing of this negative regulator has causative effect in the diversification of immune signalling and if each isoform plays a role in resolving inflammatory responses. We have developed a mouse cell model to study the function of these Tollip isoforms by over-expressing or knocking-down the variants in a macrophage-like cell line, RAW264.7. Our studies showed that endogenous Tollip.b was expressed at a very low level, whereas Tollip.a was expressed abundantly in macrophages. Over-expressing either of the Tollip isoforms caused dramatic changes in cell morphology and cell proliferation. Further investigation into LPS-responsive signalling in these recombinant cell lines revealed an altered capacity to signal through MAPK pathways, resulting in altered cytokine production.
doi:10.25904/1912/891 fatcat:fyyfpyqurnhlvlr72iazr4vu44