LPS stimulation

Jung, H. W. Chung, Y. S. Kim, Y. S. Park, Y.-K. Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kB in LPS-stimulated BV-2 microglial cells. Exp. Mol. Med. 2007, 39, 715-721. 

Verani A, Scarlatti G, Comar M, et al. C-C chemokines released by lipopolysac-charide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells. J Exp Med 1997 185(5) 805—816. 

Wang, X. C., C. Allen et al. (2007). Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J. Clin. Immunol. 27(2) 193-200. 

Heagy, W. et al., Lower levels of whole blood LPS-stimulated cytokine release are associated with poorer clinical outcomes in surgical ICU patients, Surg. Infect (Larchmt.), 4, 171, 2003. 

Monkkonen J, Pennanen N, Lapinjoki S, Urtti A. Clodronate (dichloromethy-lene bisphosphonate) inhibits LPS-stimulated IL-6 and TNF production by Raw-264 cells. Life Sci 1994 54 P1229-P1234. 

Anti-inflammatory drugs such as pentoxyfUline and dexamethasone inhibited the release of cytokines and thereby the induction of iNOS and the release of NO in the LPS-stimulated... 

Studies similar to those described above are now being carried out in human liver slices. LPS induction in human liver slices also increased TNFa production to the same extent as was found in rat liver slices [104] (Figure 12.10). Human liver slices also produced IL-6, IL-8 and IL-ip, although the latter to a lesser extent than that observed in the liver slices of rat origin. However, human liver slices produced less NO after LPS stimulation than those of the rat. More experiments will be undertaken to elucidate this species difference. 

Figure 12.9. (a) TNFa production by rat liver slices (n = 9) after stimulation with 100 pg ml LPS for 24 h in either the presence or absence of dexamethasone (D). Vehicle consists of PBS. p < 0.05 versus vehicle + LPS. (b) TNFa production by rat liver slices (n = 9) after LPS stimulation for 24 h with or without Dexaio-HSA (DH). Vehicle contains PBS and an equimolar amount of HSA. p < 0.05 versus vehicle + LPS. 

Probucol, a hypocholesterolemic drug that possesses antioxidant activity, inhibits the ex vivo release of IL-1 from LPS-stimulated macrophages of mice pretreated orally with 100 mg/kg/day of this compound [94,95]. This compound has been shown to inhibit LPS-induced zinc-lowering effect, is cited as direct evidence for the inhibition of IL-1 release, and may be useful candidate for the treatment of atherosclerosis [95,96]. An amino-dithiol-one derivative (RP 54745) blocked the proliferative action of IL-1 P on murine thymocytes in vitro and also inhibited the production of IL-1 in mouse peritoneal macrophages in vitro and in vivo. The compound RP 54745 selectively inhibited the expression of IL-la and IL-1 3 mRNA while TNFa mRNA was unaffected [97, 98]. 

ONO-1714 has reached phase II clinical trials for the treatment of hypotension and septic shock. The compound is a very potent and competitive inhibitor of the human iNOS with no selectivity over the neuronal form and 10-fold selectivity over eNOS. The compound is very active in vivo, reducing LPS-stimulated NO production in a mouse model with an ID5o value of 0.1 mg/kg s.c.. In 2000, the analgesic activity of ONO-1714 was filed by Ono Pharmaceuticals (Naka and Kobayashi). 

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