The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour.

We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J(2) (15dPGJ(2)) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-κB (NF-κB) by a mechanism yet to be elucidated. 15dPGJ(2) is an agonist of the second prostaglandin D(2) receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ(2) in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-κB, IL-1ß, KC-GRO, interferon-γ and tumour necrosis factor-α. This suggests that the action of 15dPGJ(2) is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour.

[Influence of hypoxen on acetylsalicylic acid efficiency in acute inflammation].

Rats were treated by subplantar injections of 0.1 ml 1% carrageenan solution. In 3 hours, this led to the development of acute inflammatory reaction (swelling of legs, neutrophilic leukocytosis, increased erythrocyte sedimentation rate, activation of free-radical oxidation). Acetylsalicylic acid in a dose of 100 mg/kg reduced development of the inflammatory response. Hypoxen in a dose of 50 mg/kg potentiated the effect of acetylsalicylic acid. The injection of both hypoxen and acetylsalicylic acid before the injection of carrageenan produced a strong anti-inflammatory effect, which was manifested by a reliable decrease in all monitored signs of inflammation.

Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription.

Calcitriol, the active form of vitamin D, in combination with the glucocorticoid dexamethasone (Dex) has been shown to increase the antitumor effects of calcitriol in squamous cell carcinoma. In this study we found that pretreatment with Dex potentiates calcitriol effects by inhibiting cell growth and increasing vitamin D receptor (VDR) and VDR-mediated transcription. Treatment with actinomycin D inhibits Vdr mRNA synthesis, indicating that Dex regulates VDR expression at transcriptional level. Real time PCR shows that treatment with Dex increases Vdr transcripts in a time- and a dose-dependent manner, indicating that Dex directly regulates expression of Vdr. RU486, an inhibitor of glucocorticoids, inhibits Dex-induced Vdr expression. In addition, the silencing of glucocorticoid receptor (GR) abolishes the induction of Vdr by Dex, indicating that Dex increases Vdr transcripts in a GR-dependent manner. A fragment located 5.2 kb upstream of Vdr transcription start site containing two putative glucocorticoid response elements (GREs) was evaluated using a luciferase-based reporter assay. Treatment with 100 nm Dex induces transcription of luciferase driven by the fragment. Deletion of the GRE distal to transcription start site was sufficient to abolish Dex induction of luciferase. Also, chromatin immunoprecipitation reveals recruitment of GR to distal GRE with Dex treatment. We conclude that Dex increases VDR and vitamin D effects by increasing Vdr de novo transcription in a GR-dependent manner.

[Influence of polyoxidonium on IL-1 beta, TNF-alpha and IL-6 production by mononuclears and monocytes under the dexamethasone effect].

It was established that in a mononuclear fraction polyoxidonium inhibited the TNF-alpha production and stimulated the IL-1 beta and IL-6 production. In LPS-induced mononuclear cultures polyoxidonium inhibited the IL-6 production and had no statistically significant effect on the synthesis of TNF-alpha and IL-1 beta. Polyoxidonium had no effect on TNF-alpha, IL-6 and IL-1 beta production by purified monocytes. The addition of polyoxidonium with dexamethasone to the cultures only in monocyte fraction enhanced the IL-1 beta production as compared with the effect of dexamethasone alone. Data obtained allow suggesting that under certain conditions polyoxidonium could alleviate pronounced suppressive influence of glucocorticoids on a secretory activity of effectors of innate immunity.

Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators.

A well-integrated host inflammatory response is essential in maintaining health and fighting disease. It is important to achieve a complete understanding of the cellular and molecular events that govern the resolution of acute inflammation. Because novel lipid-derived mediators, called resolvins and protectins in animal models, control the duration and magnitude of inflammation, the mapping of these resolution circuits may provide new ways of understanding the molecular basis of many inflammatory diseases. This article provides an overview of recent studies on resolvin and protectin biosynthesis and of advances in understanding the actions of these novel anti-inflammatory and proresolving lipid mediators. These new families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation identified during the natural spontaneous resolution phase. They are biosynthesized from omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) and possess potent anti-inflammatory, proresolving, and antifibrotic actions in vivo. Taken together, these findings suggest that defective resolution mechanisms may underlie the inflammatory phenotypes that are believed to characterize many common human diseases. The new families of endogenous proresolving and anti-inflammatory agonists constitute a new genus of anti-inflammatories.

Clinical tolerance and profile of cytokine induction in healthy volunteers following the simultaneous administration of ifn-alpha and the synthetic immunomodulator murabutide.

As the therapeutic use of interferon-alpha (IFN-alpha) is limited by a dose-dependent toxicity and variable efficacy, ways of improving the therapeutic index of the cytokine are being sought. Murabutide (N-acetyl muramyl-L-alanyl-D-glutamine-O-n-butyl-ester) (ISTAC Biotechnology, Lille, France) is a safe synthetic and clinically acceptable immunomodulator that enhances the biologic activities of IFN-alpha in different experimental models. We evaluated in healthy human volunteers tolerance of the coadministration of Murabutide with increasing doses of IFN-alpha. The simultaneous administration of the two drugs was well tolerated without any increased or prohibiting toxicity, and all recipients experienced side effects that were similar to those observed after the administration of IFN-alpha alone. We also profiled the serum levels of cytokines induced following coinjection of the two drugs. We mostly detected an induction of anti-inflammatory cytokines and of human immunodeficiency virus type 1 (HIV-1)-suppressive beta-chemokines, in the absence of release of key proinflammatory cytokines. Therefore, the simultaneous administration of Murabutide and IFN-alpha is well tolerated and does not lead to increased toxicity. In addition, the selectivity in the profile of cytokines and chemokines induced following the coadministration of Murabutide and IFN-alpha points to the potential use of this combination in the treatment of inflammatory diseases and chronic viral infections.

Tumor Necrosis Factor and the consequences of its ablation in vivo.

Although TNF has been discovered due to anti-tumor activity, its physiological functions are different. Current knowledge places TNF downstream of many receptors of innate immunity, implying its primary role in host defense and inflammation. When overproduced systemically or locally, TNF may exert deleterious effects on the organism. Anti-TNF therapy is highly efficient in several autoimmune and inflammatory diseases. However, due to TNF unique beneficial functions in immune system, such therapy cannot be entirely free of adverse effects. We review the current status of the field with the focus on drugs and strategies used for TNF ablation in vivo.