In this review, we present the basic properties, physiological functions, regulation, and pathological alterations of four major classes of K + channels that have been detected channels, which are expressed in smooth muscle of the small-diameter arteries, contribute to the resting membrane potential and basal tone. Kir channel activation has been shown to raise the extracellular K + concentration to 10-15 mM, resulting in vasodilation. Each of K + channels listed above is responsive to a number of vasoconstrictors and vasodilators, which act through protein kinase C (PKC) and protein kinase A (PKA), respectively. Impaired Kv, KATP, and Kir channel functions has been linked to a number of pathological conditions, which may lead to vasoconstriction.
Suppression of an excessive systemic inflammatory response is a promising and potent strategy for treating endotoxic sepsis. Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. In this study, we report a critical role for IDO in the dysregulated immune response associated with endotoxin shock. We found that IDO knockout (IDO ؊/؊ ) mice and 1-methyl-D-tryptophan-treated, endotoxin-shocked mice had decreased levels of the cytokines, TNF-␣, IL-6, and IL-12, and enhanced levels of IL-10. Blockade of IDO is thought to promote host survival in LPS-induced endotoxin shock, yet little is known about the molecular mechanisms that regulate IDO expression during endotoxin shock. In vitro and in vivo, IDO expression was increased by exogenous IL-12, but decreased by exogenous IL-10 in dendritic cells and splenic dendritic cells. Interestingly, whereas LPS-induced IL-12 levels in serum were higher than those of IL-10, the balance between serum IL-12 and IL-10 following challenge became reversed in IDO Sepsis is a systemic inflammatory response syndrome induced by microbial infection that is characterized by hemodynamic shock and multiple organ failure (1, 2). The pathogenesis of sepsis involves a progressive and dynamic expansion of a systemic inflammatory response to bacterial infection (3). Endotoxin, or LPS, is a major component of the outer membrane of Gram-negative bacteria; as such, it is an effective trigger of the inflammatory response during infection with Gram-negative bacteria. Uncontrolled activation of LPS-induced mechanisms results in sepsis. However, growing evidence supports the idea that LPS does not directly cause septic shock and tissue injury. Rather, it stimulates the production of proinflammatory cytokines, such as TNF-␣ and IL-1, which, in the context of massive infections associated with sepsis, can precipitate tissue injury and lethal shock (1, 4). It is a major cause of morbidity and mortality in hospitalized patients, yet effective treatment modalities remain elusive. Sepsis is associated with acute and systemic host immune responses; in the case of cell-mediated immune responses, the release of cytokines, such as TNF-␣, IL-1, IL-6, IL-12p70, and IFN-␥, is mechanistically involved in sepsis development (5). Immune and inflammatory systems are controlled by multiple proand anti-inflammatory cytokines, many of which are absent under normal, homeostatic conditions. However, massive bacterial infections cause the host to produce excessive amounts of proinflammatory cytokines that threaten the host's survival (6). Thus, the balance between proinflammatory and anti-inflammatory influences is likely a critical element in the mechanism of sepsis.Dendritic cells (DCs) 3 are potent APCs and provide costimulatory signals for innate and adaptive immune responses. For example, LPS promotes DC maturation and IL-12 secretion, which primes naive CD4 T cell toward a Th1 phenotype (7). In contrast, IL-10 produc...
We used proteomics to detect regional differences in protein expression levels from mitochondrial fractions of control, ischemia-reperfusion (IR), and ischemic preconditioned (IPC) rabbit hearts. Using 2-DE, we identified 25 mitochondrial proteins that were differentially expressed in the IR heart compared with the control and IPC hearts. For three of the spots, the expression patterns were confirmed by Western blotting analysis. These proteins included 3-hydroxybutyrate dehydrogenase, prohibitin, 2-oxoglutarate dehydrogenase, adenosine triphosphate synthases, the reduced form of nicotinamide adenine dinucleotide (NADH) oxidoreductase, translation elongation factor, actin alpha, malate dehydrogenase, NADH dehydrogenase, pyruvate dehydrogenase and the voltage-dependent anion channel. Interestingly, most of these proteins are associated with the mitochondrial respiratory chain and energy metabolism. The successful use of multiple techniques, including 2-DE, MALDI-TOF-MS and Western blotting analysis demonstrates that proteomic analysis provides appropriate means for identifying cardiac markers for detection of ischemia-induced cardiac injury.
Background and purpose:Cilostazol is a specific inhibitor of 3′-5′-cyclic adenosine monophosphate (cAMP) phosphodiesterase, which is widely used to treat ischemic symptoms of peripheral vascular disease. Although cilostazol has been shown to exhibit vasodilator properties as well as antiplatelet and anti-inflammatory effects, its cellular mechanism in microglia is unknown. In the present study, we assessed the anti-inflammatory effect of cilostazol on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated murine BV2 microglia. Experimental approach: We examined the effects of cilostazol on LPS-induced nuclear factor-kappaB (NF-kB) activation and phosphorylation of mitogen-activated protein kinases (MAPKs). Key results: Cilostazol suppressed production of nitric oxide (NO), prostaglandin E2 (PGE2) and the proinflammatory cytokines, interleukin-1 (IL-1), tumour necrosis factor-a, and monocyte chemoattractant protein-1 (MCP-1), in a concentrationdependent manner. Inhibitory effects of cilostazol were not affected by treatment with an adenylate cyclase inhibitor, SQ 22536, indicating that these actions of cilostazol were cAMP-independent. Cilostazol significantly inhibited the DNA binding and transcriptional activity of NF-kB. Moreover, cilostazol blocked signalling upstream of NF-kB activation by inhibiting extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but without affecting the activity of p38 MAPK. Conclusion and implications:Our results demonstrate that suppression of the NF-kB, ERK, JNK signalling pathways may inhibit LPS-induced NO and PGE2 production. Therefore, cilostazol may have therapeutic potential for neurodegenerative diseases by inhibiting pro-inflammatory mediators and cytokine production in activated microglia. (2010) 159, 1274-1285; doi:10.1111/j.1476-5381.2009.00615.x; published online 28 January 2010 British Journal of PharmacologyKeywords: cilostazol; inducible nitric oxide synthase; cyclooxygenase-2; nuclear factor-kB; monocyte chemoattractant protein-1; cAMP Abbreviations: COX-2, cyclooxygenase-2; IKK, IkB kinase; IL-1b, interleukin-1b; iNOS, inducible nitric oxide synthase; IkB, inhibitor of NF-kB; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MEKK1, MAPK/ERK kinase kinase 1; NF-kB, nuclear factor-kB; PGE2, prostaglandin E2; SEK1/MKK4, SAPK/ERK1/ MAPK kinase kinase 4; TNF-a, tumour necrosis factor-a
A key factor in dendritic cell (DC)-based tumor immunotherapy is the identification of an immunoadjuvant capable of inducing DC maturation to enhance cellular immunity. The efficacy of a 50S ribosomal protein L7/L12 (rplL) from Mycobacterium tuberculosis Rv0652, as an immunoadjuvant for DC-based tumor immunotherapy, and its capacity for inducing DC maturation was investigated. In this study, we showed that Rv0652 is recognized by Toll-like receptor 4 (TLR4) to induce DC maturation, and pro-inflammatory cytokine production (TNF-alpha, IL-1beta, and IL-6) that is partially modulated by both MyD88 and TRIF signaling pathways. Rv0652-activated DCs could activate naïve T cells, effectively polarize CD4+ and CD8+ T cells to secrete IFN-gamma, and induce T cell-mediated-cytotoxicity. Immunization of mice with Rv0652-stimulated ovalbumin (OVA)-pulsed DCs resulted in induction of a potent OVA-specific CD8+ T cell response, slowed tumor growth, and promoted long-term survival in a murine OVA-expressing E.G7 thymoma model. These findings suggest that Rv0652 enhances the polarization of T effector cells toward a Th1 phenotype through DC maturation, and that Rv0652 may be an effective adjuvant for enhancing the therapeutic response to DC-based tumor immunotherapy.
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