Etanercept is a tumor necrosis factor antagonist with antiinflammatory effects. The aim of our study was to evaluate for the first time the therapeutic efficacy of in vivo inhibition of tumor necrosis factor-␣ (TNF-␣) in experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T 5 -T 8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production that it is followed by recruitment of other inflammatory cells, such as production of a range of inflammation mediators, tissue damage, apoptosis, and disease. Treatment of the mice with etanercept significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase evaluation); 3) inducible nitric-oxide synthase, nitrotyrosine, cyclooxygenase-2, and cytokines expression (TNF-␣ and interleukin-1␤); and 4) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and Bax and Bcl-2 expression). In a separate set of experiment, we have also clearly demonstrated that TNF-␣ inhibitor significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with etanercept reduces the development of inflammation and tissue injury events associated with spinal cord trauma.

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Glucocorticoid-induced TNFR-related gene (GITR) participates in the immune/inflammatory response. Because GITR expression has been described in cells other than T lymphocytes, we investigated whether it also modulates acute inflammatory response. Using GITR-deficient (GITR−/−) mice, we analyzed the role of GITR in the development of carrageenan-induced lung inflammation (pleurisy) by studying several proinflammatory markers 2–8 h after carrageenan injection. When compared with GITR+/+, GITR−/− mice exhibited decreased production of turbid exudate containing a lower number of leukocytes. This was correlated with the reduction of inflammatory markers (including TNF-α, IL-1β, myeloperoxidase, inducible NO synthase, and cyclooxygenase 2) in the pleural exudate and/or in the lung. Moreover, endothelial cells expressed lower levels of adhesion molecules. In lungs of GITR+/+ mice, GITR ligand expression was not modulated during pleurisy, while that of GITR increased, as a consequence of increased infiltration by GITR-expressing cells and of GITR up-regulation in macrophages and endothelial cells. Finally, cotreatment of GITR+/+ mice with carrageenan and Fc-GITR fusion protein decreased the number of inflammatory cells (pleural macrophages and lung neutrophils) as compared with carrageenan treatment alone, confirming that GITR plays a role in the modulation of pleurisy.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study was to evaluate the role of the PPAR-alpha receptor on the development of acute inflammation. To address this question, we used two animal models of acute inflammation (carrageenan-induced paw edema and carrageenan-induced pleurisy). We report here that when compared with PPAR-alpha wild-type mice, PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity when subjected to carrageenan injection in the paw edema model or to carrageenan administration in the pleurisy model. In particular, the absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of various inflammatory parameters (e.g., enhancement of paw edema, pleural exudate formation, mononuclear cell infiltration, and histological injury) in vivo. Furthermore, the absence of a functional PPAR-alpha gene enhanced the staining (immunohistochemistry) for FAS ligand in the paw and in the lung and the expression of tumor necrosis factor alpha and interleukin-1beta in the lungs of carrageenan-treated mice. In conclusion, the increased inflammatory response observed in PPAR-alphaKO mice strongly suggests that a PPAR-alpha pathway modulates the degree of acute inflammation in the mice.

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Up to 60% of depressed patients do not respond completely to antidepressants (ADs) and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 superfamily, the P-glycoprotein (ABCB1), the tryptophan hydroxylase, the catechol-Omethyltransferase, the monoamine oxidase A, the serotonin transporter (5-HTTLPR), the norepinephrine transporter, the dopamine transporter, variants in the 5-hydroxytryptamine receptors (5-HT1A, 5-HT2A, 5-HT3A, 5-HT3B, and 5-HT6), adrenoreceptor beta-1 and alpha-2, the dopamine receptors (D2), the G protein beta 3 subunit, the corticotropin releasing hormone receptors (CRHR1 and CRHR2), the glucocorticoid receptors, the c-AMP response-element binding, and the brain-derived neurotrophic factor. Marginal associations were reported for angiotensin I converting enzyme, circadian locomotor output cycles kaput protein, glutamatergic system, nitric oxide synthase, and interleukin 1-beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene × environment interactions have been hypothesized to modulate several of these effects.

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Various evidences have documented that the pineal secretory product melatonin exerts an important anti-inflammatory effect in different experimental models including colitis. The aim of the present study was to evaluate whether melatonin regulates the inflammatory response of experimental colitis in rats at the level of signal transduction pathway. Colitis was induced by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Four days after DNBS administration, a substantial increase of colon TNF-alpha production was associated with the colon damage. In DNBS-treated rats, the colon injury correlated with a significant rise of apoptosis (evaluated by TUNEL coloration) which was associated with a significant increased expression of proapoptotic Bax and decreased colon content of antiapoptotic Bcl-2. This inflammatory response was also related to activation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun as well as FAS ligand expression in the colon. Treatment with melatonin (15 mg/kg daily i.p.) was associated with a remarkable amelioration of colonic disrupted architecture as well as a significant reduction of TNF-alpha. Melatonin also reduced the NF-kappaB activation and phosphorylation of c-Jun as well as the Fas ligand expression in the colon. Furthermore, melatonin reduced the expression of Bax and prevented the loss of Bcl-2 proteins as well as the presence of apoptotic cells caused by DNBS. The results of this study show that melatonin administration exerts beneficial effects in inflammatory bowel disease by modulating signal transduction pathways.