Tribbles-2 is a novel regulator of inflammatory activation of monocytes.

Inflammatory activation of monocytes is an essential part of both innate immune responses and the pathogenesis of conditions such as atherosclerosis. However, the mechanisms which modulate the response of monocytes to inflammatory stimuli are still poorly understood. Here, we report that tribbles-2 (trb-2) is a novel regulator of inflammatory activation of monocytes. Down-regulation of trb-2 levels potentiates LPS-induced IL-8 production via enhanced activation of the extracellular signal-regulated kinase and jun kinase mitogen-activated protein kinase (MAPK) pathways. In keeping with this, the endogenous level of trb-2 expression in human primary monocytes is inversely correlated to the cell's ability to produce IL-8. We show that trb-2 is a binding partner and a negative regulator of selected MAPKs. The potential in vivo relevance of these findings is highlighted by the observation that modified low-density lipoprotein profoundly down-regulates trb-2 expression, which may, in turn, significantly contribute to the inflammatory processes in the development of vascular disease. Taken together, our results define trb-2 as a potent novel regulator of monocyte biology, controlling the activation of these cells.

LDL uptake by monocytes in response to inflammation is MAPK dependent but independent of tribbles protein expression.

Inflammatory activation of monocytes is a hallmark event in cardiovascular disease. Activated monocytes migrate into atherosclerotic lesions, differentiate into macrophages and ingest lipids to become foam cells. These, in turn, through interaction with other inflammatory cell types contribute to plaque instability and are thought to play a key role in the development of acute coronary syndromes. In the current manuscript we investigated whether inflammatory activation of monocyte THP-1 cells influences their ability to take-up chemically modified LDL. We have also studied whether tribbles proteins, which have been shown to regulate the activation of inflammatory signal processing networks, have a modulatory role in the uptake of modified LDL by monocyte. Here, we show that activation of THP-1 cells by LPS potentiates LDL uptake. The greatest effect of LPS was seen after 16 h, compared to acute stimulation. Specific MAPK pathways are involved in this potentiation. Inhibition of both the p38 and ERK pathways led to reduced LPS uptake, specifically in LPS stimulated cells. Expression of tribbles, regulators of MAPK signalling, was dynamically modulated by LPS activation. However, neither suppression of tribbles expression by transient transfection of specific siRNAs nor transient overexpression of these proteins led to changes in the capacity of THP-1 cells to take up modified LDL. Therefore, we conclude that LPS potentiation of LDL uptake of THP-1 cells is MAPK dependent but is not mediated by tribbles.

Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.

Control of mitogen-activated protein kinase (MAPK) cascades is central to regulation of many cellular responses. We describe here human tribbles homologues (Htrbs) that control MAPK activity. MAPK kinases interact with Trbs and regulate their steady state levels. Further, Trbs selectively regulate the activation of extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and p38 MAPK with different relative levels of activity for the three classes of MAPK observed depending on the level of Trb expression. These results suggest that Trbs control both the extent and the specificity of MAPK kinase activation of MAPK.