Involvement of both the tyrosine kinase and the phosphatidylinositol-3 ' kinase signal transduction pathways in the regulation of lipoprotein lipase expression in J774.2 macrophages by cytokines and lipopolysaccharide

The regulation of macrophage lipoprotein lipase (LPL) by cytokines and lipopolysaccharide (LPS) is of potentially crucial importance in the pathogenesis of atherosclerosis and in the responses to endotoxin challenge. We show here that the reduction of LPL activity in J774.2 macrophages observed in the presence of interleukin (IL-1) and IL-11 was sensitive to herbimycin A, with the effect of LPS, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) on LPL activity being sensitive to both herbimycin A and wortmannin. The action of the inhibitors on the IFN-γ-dependent reduction of LPL activity was mediated at the level of LPL mRNA metabolism, with translational and/or post-translational levels of regulation being involved in the action of all the other mediators tested. These observations suggest that both the tyrosine kinase and the phosphatidylinositol-3′-kinase signalling pathways are involved in the suppression of macrophage LPL expression by LPS and cytokines

Synergism between lipopolysaccharide and interferon gamma in the regulation of lipoprotein lipase in macrophages

The regulation of macrophage lipoprotein lipase (LPL) by cytokines is potentially of crucial importance in the pathogenesis of atherosclerosis and in septic shock. The effect of combinations of lipopolysaccharide (LPS) and cytokines on the expression of LPL in macrophages was studied using the murine J774.2 cell line. The suppression of heparin-releasable LPL activity produced by combinations of LPS and interleukin 1 (IL-1), IL-11 or tumour necrosis factor α(TNF-α) was substantially less than that expected from the simple additive action of the corresponding two effectors. By contrast, co-exposure of the cells to LPS and interferon γ(IFN-γ) resulted in a more than additive, synergistic, suppression of LPL activity which was, additionally, also observed when the rat alveolar macrophage NR8383 cell line was studied. This synergistic action was also observed when J774.2 macrophages were exposed initially to IFN-γ (priming), washed and then treated with LPS. A comparison of the LPL activity and mRNA levels produced by the synergistic action of LPS and IFN-γand the priming action of IFN-γ indicated that a combination of mRNA metabolism (transcription or RNA stability), translation and post-translational mechanisms were responsible for the observed changes in LPL activity. These data, therefore, suggest that combinations of LPS and cytokines may be more important than the presence or absence of any given single effector in the modulation of LPL function during infection

A novel role of Sp1 and Sp3 in the interferon- -mediated suppression of macrophage lipoprotein lipase gene transcription

The regulation of macrophage lipoprotein lipase by cytokines is of potentially crucial importance in the pathogenesis of atherosclerosis. We have shown previously that macrophage lipoprotein lipase expression is suppressed by interferon-γ (IFN-γ) at the transcriptional level. We investigated the regulatory sequence elements and the transcription factors that are involved in this response. We demonstrated that the −31/+187 sequence contains the minimal IFN-γ-responsive elements. Electrophoretic mobility shift assays showed that the binding of proteins to two regions in the −31/+187 sequence was reduced dramatically when the cells were exposed to IFN-γ. Both competition electrophoretic mobility shift assays and antibody supershift assays showed that the interacting proteins were composed of Sp1 and Sp3. Mutations of the Sp1/Sp3-binding sites in the minimal IFN-γ-responsive elements abolished the IFN-γ-mediated suppression of promoter activity, whereas multimers of the sequence were able to impart the response to a heterologous promoter. Western blot analysis showed that IFN-γ reduced the steady state levels of Sp3 protein. In contrast, the cytokine decreased the DNA binding activity of Sp1 without affecting the protein levels. These studies therefore reveal a novel mechanism for IFN-γ-mediated regulation of macrophage gene transcription

Deep Cerebral Venous Thrombosis—A Clinicoradiological Study

Stroke is a common neurological emergency. Almost 80% of strokes are due to arterial occlusion. Venous thrombosis comprises less than 1–2% of all strokes. Involvement of the deep cerebral venous system is still rare and accounts for about 10.9% of all cerebral venous thromboses (CVT). CVT diagnosis is often delayed or missed, because of its variable clinical manifestations. We retrospectively (2015–18) and prospectively (2018–20) reviewed all the cases of CVT in a tertiary care center in south India. Out of a total of 52 CVT cases, 12 were due to the involvement of deep cerebral venous system. Their clinical presentation, imaging characteristics, and outcomes were assessed. The most frequent presentation was headache followed by seizures. Hyperhomocysteinemia was the most common risk factor noted. Imaging characteristics were variable, and a high index of suspicion was required for early diagnosis. All patients had favorable outcome in our study, and except one, all were treated conservatively