51 research outputs found
Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium.
BACKGROUND: The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. RESULTS: Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition. CONCLUSIONS: These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation
Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells
The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering β-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization. siRNA inhibition of anterograde intraflagellar transport (IFT88) reduced cilia length and increased active nuclear β-catenin. Conversely, increased primary cilia assembly in MSCs cultured on the grooves was associated with decreased levels of nuclear active β-catenin, axin-2 induction and proliferation, in response to wnt3a. This negative regulation, on grooved topography, was reversed by siRNA to IFT88. This indicates that subtle regulation of IFT and associated cilia structure, tunes the wnt response controlling stem cell differentiation.We acknowledge funding from an EPSRC Platform grant which supported McMurray and a Wellcome Trust project grant which supported Wann and McMurray. Wann is now supported on an ARUK project grant. Thompson was funded by a BBSRC PhD studentshi
Prolonged Depression-Like Behavior Caused by Immune Challenge: Influence of Mouse Strain and Social Environment
Immune challenge by bacterial lipopolysaccharide (LPS) causes short-term
behavioral changes indicative of depression. The present study sought to explore
whether LPS is able to induce long-term changes in depression-related behavior
and whether such an effect depends on mouse strain and social context. LPS (0.83
mg/kg) or vehicle was administered intraperitoneally to female CD1 and C57BL/6
mice that were housed singly or in groups of 4. Depression-like behavior was
assessed with the forced swim test (FST) 1 and 28 days post-treatment.
Group-housed CD1 mice exhibited depression-like behavior 1 day post-LPS, an
effect that leveled off during the subsequent 28 days, while the behavior of
singly housed CD1 mice was little affected. In contrast, singly housed C57BL/6
mice responded to LPS with an increase in depression-like behavior that was
maintained for 4 weeks post-treatment and confirmed by the sucrose preference
test. Group-housed C57BL/6 mice likewise displayed an increased depression-like
behavior 4 weeks post-treatment. The behavioral changes induced by LPS in
C57BL/6 mice were associated with a particularly pronounced rise of
interleukin-6 in blood plasma within 1 day post-treatment and with changes in
the dynamics of the corticosterone response to the FST. The current data
demonstrate that immune challenge with LPS is able to induce prolonged
depression-like behavior, an effect that depends on genetic background (strain).
The discovery of an experimental model of long-term depression-like behavior
after acute immune challenge is of relevance to the analysis of the epigenetic
and pathophysiologic mechanisms of immune system-related affective
disorders
Supplemental vibrotactile feedback control of stabilization and reaching actions of the arm using limb state and position error encodings
Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model
Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14–16, 2010, São Paulo, Brazil
Sex differences in depression-like behavior and neuroinflammation in rats post-MI: role of estrogens
Reduction of oxidative stress during recovery accelerates normalization of primary cilia length that is altered after ischemic injury in murine kidneys
Mechanical loading inhibits cartilage inflammatory signalling via an HDAC6 and IFT-dependent mechanism regulating primary cilia elongation.
OBJECTIVE: Physiological mechanical loading reduces inflammatory signalling in numerous cell types including articular chondrocytes however the mechanism responsible remains unclear. This study investigates the role of chondrocyte primary cilia and associated intraflagellar transport (IFT) in the mechanical regulation of interleukin-1β (IL-1β) signalling. DESIGN: Isolated chondrocytes and cartilage explants were subjected to cyclic mechanical loading in the presence and absence of the cytokine IL-1β. Nitric oxide (NO) and PGE2 release were used to monitor IL-1β signalling whilst sGAG release provided measurement of cartilage degradation. Measurements were made of HDAC6 activity and tubulin polymerisation and acetylation. Effects on primary cilia were monitored by confocal and super resolution microscopy. Involvement of IFT was analysed using ORPK cells with hypomorphic mutation of IFT88. RESULTS: Mechanical loading supressed NO and PGE2 release and prevented cartilage degradation. Loading activated HDAC6 and disrupted tubulin acetylation and cilia elongation induced by IL-1β. HDAC6 inhibition with tubacin blocked the anti-inflammatory effects of loading and restored tubulin acetylation and cilia elongation. Hypomorphic mutation of IFT88 reduced IL-1β signalling and abolished the anti-inflammatory effects of loading indicating the mechanism is IFT-dependent. Loading reduced the pool of non-polymerised tubulin which was replicated by taxol which also mimicked the anti-inflammatory effects of mechanical loading and prevented cilia elongation. CONCLUSIONS: This study reveals that mechanical loading suppresses inflammatory signalling, partially dependent on IFT, by activation of HDAC6 and post transcriptional modulation of tubulin
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