Journal of leukocyte biology
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During acquired immunity to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in mice, dendritic cells (DCs) present mycobacterial antigens to naive T cells to prime an immune response. Complement C5a (anaphylatoxin) secreted by mycobacteria-infected macrophages regulates IL-12p70 production. As IL-12p70 regulates Th1 immunity against mycobacteria in mice, we examined the effects of C5a on IL-12p70 secretion by murine DCs and Th1 immunity. ⋯ Thus, BCG-primed C5(+/+) DCs were better able to drive a Th1 response. Furthermore, BCG aerosol-infected C5(-/-) mice showed reduced CD4 and CD8 IFN-gamma-secreting T cells in the lungs, concurrent with an increased growth of BCG. Thus, C5a, an innate peptide, appears to play an important role in the generation of acquired immune responses in mice by regulating the Th1 response through modulation of IL-12p70 secretion from DCs.
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Hydrogen sulfide (H(2)S) is recognized increasingly as a proinflammatory mediator in various inflammatory conditions. Here, we have investigated the role of H(2)S in regulating expression of some endothelial adhesion molecules and recruitment of leukocytes to inflamed sites in sepsis. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with saline (i.p.), DL-propargylglycine (PAG; 50 mg/kg, i.p.), an inhibitor of H(2)S formation or NaHS (10 mg/kg, i.p.), an H(2)S donor. ⋯ These alterations were reversed by pretreatment with BAY 11-7082. Moreover, expression of CXCR2 in neutrophils obtained from H(2)S-treated mice was up-regulated significantly, leading to an obvious elevation in MIP-2-directed migration of neutrophils. Therefore, H(2)S acts as an important endogenous regulator of leukocyte activation and trafficking during an inflammatory response.
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As studies indicate that genomic and nongenomic pathways are involved in mediating the salutary effects of 17beta-estradiol (E2) following trauma-hemorrhage, we examined if the nongenomic effects of E2 on attenuation of intestinal injury after trauma-hemorrhage involve the PI-3K/Akt pathway. Male Sprague-Dawley rats ( approximately 300 g body weight) underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min), followed by resuscitation. E2 conjugated to BSA (E2-BSA; 1 mg/Kg E2), with or without an estrogen receptor antagonist (ICI 182,780), a PI-3K inhibitor (Wortmannin), or vehicle, was injected i.v. during resuscitation. ⋯ Although trauma-hemorrhage decreased intestinal PI-3K and p-Akt protein expressions, E2 or E2-BSA treatment following trauma-hemorrhage prevented such decreases in intestinal PI-3K and p-Akt protein expressions. Coadministration of ICI 182,780 or Wortmannin abolished the beneficial effects of E2-BSA on attenuation of intestinal injury following trauma-hemorrhage. Thus, the PI-3K/Akt pathway plays a critical role in mediating the nongenomic, salutary effects of E2 on attenuation of shock-induced intestinal tissue damage.
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Earlier work from our laboratory has suggested a role for the neuropeptide substance P (SP) in inducing lung injury in sepsis. In that study, mice lacking the preprotachykinin-A gene, which encodes for SP, were protected against lung injury in sepsis. To further substantiate the role of SP in sepsis and to study its mechanism, we have evaluated the effect of SR140333, a SP receptor antagonist, on lung injury in sepsis, which was induced in male Swiss mice by cecal ligation and puncture (CLP). ⋯ SR140333 injected 30 min before or 1 h after CLP significantly attenuated the increased lung MPO activity and levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, and E- and P-selectin compared with CLP-operated mice injected with the vehicle. Histological evaluation of the lung sections further supported the beneficial effect of SR140333 on lung inflammation. Therefore, SP receptor antagonism can be a potential therapeutic target in polymicrobial sepsis, and this effect is brought about via reduction in leukocyte recruitment.
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Some cells, including neutrophils, accumulate high intracellular ascorbate concentrations, which suggests that they have an important function in these cells. In this study we have used L-gulono-gamma-lactone oxidase (Gulo)-/- mice, which are unable to synthesize ascorbate, to generate ascorbate-deficient neutrophils and have used these to investigate the effect of ascorbate on neutrophil function. Peritoneal neutrophils from ascorbate-deficient animals had normal morphology and respiratory burst activity but failed to undergo spontaneous apoptosis, determined by morphology and the surface expression of phosphatidylserine. ⋯ Neutrophils from Gulo-/- mice had elevated levels of hypoxia-inducible factor (HIF)-1alpha, a transcription factor regulated by Fe2+-dependent hydroxylases which require ascorbate for optimal activity. HIF-1alpha has been shown previously to inhibit neutrophil apoptosis under hypoxic conditions. Our results suggest that in ascorbate deficiency, up-regulation of HIF-1alpha blocks neutrophil apoptosis under normoxic conditions and that this represents a novel and important function for vitamin C in inflammatory cells.