Nitric-oxide synthases proinflammatory

Figure 6. Comparative gene expression ratios in ARF kidneys of MSC- and vehicle-treated animals. Data were generated by referencing each gene to p-actin as internal control. A MSC treatment cansed significant (P < 0.05) suppression (> 10 fold) of proinflammatory IL-ip, TNF a, and IFN-y (above bars actnal valnes). Anti-inflammatory lL-10 was robustly expressed in MSC-and not in vehicle treated animals. Filled bars on all panels depict gene expression ratio of 1, i.e., a value obtained when gene expression ratios between MSC- and vehicle-treated animals are "equal. B MSC treatment cansed increased gene expression of bFGF and TGF-a, whereas that of HGF was suppressed. C antiapoptotic Bcl-2 expression was robnstly indnced, whereas that of inducible nitric oxide synthase (iNOS) was snppressed in MSC- vs. vehicle-treated animals. eNOS, endothelial NOS.

Holguin, A., O sConnor, K. A., Biedenkapp, J., Campisi, J., Wieseler-Frank, J., Milligan, E. D., Hansen, M. K., Spataro, L., Maksimova, E., Bravmann, C., Martin, D., Fleshner, M., et al. (2004). HIV-1 gpl20 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). Pain 110, 517—530. 

Jana M, Anderson JA, Saha RN, Liu X, Pahan K (2005) Regulation of inducible nitric oxide synthase in proinflammatory cytokine-stimulated human primary astrocytes. Free Radic Biol Med 38 655-664. 

The innate pro-inflammatory response of these cells is activated upon exposure to LPS, prostaglandin or other TLR ligands, leading to production of classical proinflammatory cytokines including tumor necrosis factor (TNF)-a. On the other hand, classical activation by interferon (fFN)- /andLPS leads to production of TNF-a and also increased secretion of reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). 

Cho S, Kim Y, Guz MO, Park EM, Chu CK, Song GY, Joh TH (2001) Repression of proinflammatory cytokine and inducible nitric oxide synthase (NOS2) gene expression in activated microglia by N-acetyl-0-methyldopamine Protein kinase A-dependent mechanism. Glia 33 324-333. 

Kim WK, Jang PG, Woo MS, Han lO, Piao HZ, Lee K, Lee H, Joh TH, Kim HS (2004) A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuro-pharmacology 47 243—252. 

Sunyer T, Rothe L, Jiang X, et al. Proinflammatory agents, IL-8 and IL-10, upregulate inducible nitric oxide synthase expression and nitric oxide production in avian osteoclast-like cells. J Cell Biochem 1996 60 469-83. 

NF-kB regulates many genes involved in inflammation, such as inducible nitric oxide synthase (iNOS), proinflammatory cytokines, IL-1, mmor necrosis factor-alpha (TNF-a), IL-6, chemokine, IL-8, E-selectin, vascular cell adhesion molecule 1 (ICAM-1), and granulocyte-macrophage colony stimulating factor (GM-CSF) (Brennan et al., 1995 Akira and Kishimoto, 1997 Bames and Adcock, 1998 Rahman and MacNee, 1998 McClintock et al., 2002). Arroyo et al. (2000) found a dose-dependent increase in TNF-a, IL-6, and interleukin-1-beta (IL-1-beta) in SM-treated human keratinocyte cells. 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of... 

We demonstrated that BK is an important mediator of EPR effect in cancer [36]. Figure 5 shows network of BK and other mediators involving in EPR effect. BK interacts with various proinflammatory factors involving vascular permeability. For instance, it is also known to activate endothelial cell-type nitric oxide synthase (eNOS), which is one of the primary enzymes to produce NO from L-arginine. We have reported that the BK-generating cascade is activated in tumor tissues [36]. More importantly, malignant ascetic and pleural fluids would be caused by activation of kallikrein-kinin system in carcinomatosis [37]. 

Although we generally assume that the pathophysiolc ical alterations in inflammation are related to the activation of PARP-1, the major isoform of PARP, there are emetging data, in the field of colitis, that implicate a role for another isoform, PARP-2. In a murine study, conducted in the lL-10 deficient mice which develop spontaneous colitis, a chemically modified 2 -0-(2-methoxy)ethyl antisense o%onucleotide inhibitor of PARP-2 normalized colonic epithelial barrier and transport function, reduced proinflammatory cytokine secretion and inducible nitric-oxide synthase activity, and attenuated inflammation." ... 

Most recently, studies have shown that at least 50% of the neurons innervating the LES possess nitric oxide synthase, thus implicating nitric oxide as a possible mediator in relaxation of the LES. In an animal model, the LES can be induced to contract or relax when exposed to arachidonic acid and its metabolites. Because arachidonic acid is produced by the action of phospholipase Az and is a precursor of prostaglandins and leukotrienes, these proinflammatory substances may also be implicated in LES pathology. 

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