Cristina Meazza

Corticosteroid-independent inhibition of tumor necrosis factor production by the neuropeptide urocortin

Urocortin (UCN) is a neuropeptide homologous with corticotropin-releasing factor (CRF), which has anti-inflammatory activities not all mediated by corticosteroids. In mice, UCN (1 microg/mouse sc) significantly reduced lipopolysaccharide (LPS)-induced serum tumor necrosis factor (TNF) and interleukin (IL)-1beta levels in vivo but did not affect serum IL-6. These effects were paralleled by a rise in corticosterone (CS) levels. Blockade of the CS increase by cyanoketone did not prevent TNF inhibition by UCN, suggesting the neuropeptide has anti-inflammatory mechanisms independent of the hypothalamus-pituitary-adrenal axis. In fact UCN had a direct inhibitory effect on LPS-induced TNF in rat Kupffer cells at concentrations between 10(-10) and 10(-16) M, and this effect was related to increased cAMP levels. However, the in vivo inhibition of LPS-induced IL-1beta by UCN was reversed by cyanoketone, indicating that the increase of endogenous glucocorticoids might be more important in IL-1beta inhibition than in TNF inhibition by UCN.Urocortin (UCN) is a neuropeptide homologous with corticotropin-releasing factor (CRF), which has anti-inflammatory activities not all mediated by corticosteroids. In mice, UCN (1 μg/mouse sc) significantly reduced lipopolysaccharide (LPS)-induced serum tumor necrosis factor (TNF) and interleukin (IL)-1β levels in vivo but did not affect serum IL-6. These effects were paralleled by a rise in corticosterone (CS) levels. Blockade of the CS increase by cyanoketone did not prevent TNF inhibition by UCN, suggesting the neuropeptide has anti-inflammatory mechanisms independent of the hypothalamus-pituitary-adrenal axis. In fact UCN had a direct inhibitory effect on LPS-induced TNF in rat Kupffer cells at concentrations between 10-10 and 10-16 M, and this effect was related to increased cAMP levels. However, the in vivo inhibition of LPS-induced IL-1β by UCN was reversed by cyanoketone, indicating that the increase of endogenous glucocorticoids might be more important in IL-1β inhibition than in TNF inhibition by UCN.

Granulocyte Colony-Stimulating Factor and Antibiotics in the Prophylaxis of a Murine Model of Polymicrobial Peritonitis and Sepsis

Infections that occur after intraabdominal surgery still cause considerable morbidity and mortality despite the administration of prophylactic antibiotics. Increasing the number of neutrophils may also be a prophylactic approach, and granulocyte colony-stimulating factor (G-CSF) has been found to be beneficial in different animal models of peritonitis and sepsis. It is the combination of G-CSF and antibiotics, however, that is clinically relevant. Treatment of mice with G-CSF that was started before cecal ligation and puncture and continued afterward with antibiotics improved survival, decreased splenic bacterial colony-forming units and serum tumor necrosis factor, and increased serum interleukin-10, compared with treatment with antibiotics alone or with saline. Compared with saline, antibiotics alone increased tumor necrosis factor and did not affect interleukin-10. Thus, G-CSF confers onto antibiotics beneficial antiinfectious and antiinflammatory properties. A prophylactic regimen combining G-CSF and antibiotics may help prevent severe infectious complications following intraabdominal surgery.

Inhibition of systemic inflammation by central action of the neuropeptide alpha-melanocyte- stimulating hormone.

The neuropeptide α-melanocyte stimulating hormone (α-MSH) reduces fever and acute inflammation in the skin when administered centrally. The aim of the present research was to determine whether central α-MSH can also reduce signs of systemic inflammation in mice with endotoxemia. Increases in serum tumor necrosis factor-α and nitric oxide, induced by intraperitoneal administration of endotoxin, were modulated by central injection of a small concentration of α-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central α-MSH. Lung myeloperoxidase activity, a marker of neutrophil infiltration, was increased in endotoxemic mice; the increase was significantly less in lungs of mice treated with central α-MSH. Intraperitoneal administration of the small dose of α-MSH that was effective centrally did not alter any of the markers of inflammation. In experiments using immunoneutralization of central α-MSH, we tested the idea that endogenous peptide induced within the brain during systemic inflammation modulates host responses to endotoxic challenge in peripheral tissues. The data showed that proinflammatory agents induced by endotoxin in the circulation, lungs, and liver were significantly greater after blockade of central α-MSH. The results suggest that anti-inflammatory influences of neural origin that are triggered by α-MSH could be used to treat systemic inflammation.

Leptin causes body weight loss in the absence of in vivo activities typical of cytokines of the IL-6 family

To investigate if leptin shares in vivo activities with interleukin (IL)-6 family cytokines, it was tested in normal mice for the ability, after a single injection, to induce the acute-phase protein serum amyloid A, to potentiate the induction by IL-1 of serum corticosterone and IL-6, and to inhibit the induction by lipopolysaccharide of serum tumor necrosis factor and, after seven daily injections, to cause body weight loss and to change peripheral blood cell counts. At a 0.5 mg/kg dose, leptin caused body weight loss but did not show any of the other activities above. At a dose of 5 mg/kg, which also caused body weight loss, leptin potentiated the induction by IL-1 of serum corticosterone and IL-6 but did not show any other activity. In addition to causing body weight loss, leptin shows only some of the in vivo activities typical of IL-6 family cytokines and only if used at a dose that exceeds the one sufficient to affect body weight. In vivo, leptin seems to chiefly control body weight and not inflammatory or hematopoietic processes.To investigate if leptin shares in vivo activities with interleukin (IL)-6 family cytokines, it was tested in normal mice for the ability, after a single injection, to induce the acute-phase protein serum amyloid A, to potentiate the induction by IL-1 of serum corticosterone and IL-6, and to inhibit the induction by lipopolysaccharide of serum tumor necrosis factor and, after seven daily injections, to cause body weight loss and to change peripheral blood cell counts. At a 0.5 mg/kg dose, leptin caused body weight loss but did not show any of the other activities above. At a dose of 5 mg/kg, which also caused body weight loss, leptin potentiated the induction by IL-1 of serum corticosterone and IL-6 but did not show any other activity. In addition to causing body weight loss, leptin shows only some of the in vivo activities typical of IL-6 family cytokines and only if used at a dose that exceeds the one sufficient to affect body weight. In vivo, leptin seems to chiefly control body weight and not inflammatory or hematopoietic processes.

Centrally Mediated Inhibition of Local Inflammation by Ciliary Neurotrophic Factor

Since ciliary neurotrophic factor (CNTF) inhibits the production of TNF and activates the hypothalamus-pituitary-adrenal axis (HPAA), we investigated whether CNTF can produce antiinflammatory actions and whether it may act through a central mechanism, using the murine air pouch model of inflammation. In this model, inflammation is evaluated by measuring the induction of TNF and IL-6 as well as cell recruitment in the pouch fluid 24 h after carrageenan. Intracerebroventricular injection, but not intravenous or local injection of CNTF markedly inhibited inflammation. This was associated with high serum corticosterone levels, and antiinflammatory action was not observed in adrenalectomized mice, indicating that an intact HPAA is required. A CNTF receptor antagonist increased carrageenan inflammation, suggesting that endogenous CNTF might have a centrally mediated antiinflammatory role.