Anti‐inflammatory activity of cationic lipids

Abstract

1 The e ect of liposome phospholipid composition has been assumed to be relatively unimportant because of the presumed inert nature of phospholipids. 2 We have previously shown that cationic liposome formulations used for gene therapy inhibit, through their cationic component, the synthesis by activated macrophages of the pro-in¯ammatory mediators nitric oxide (NO) and tumour necrosis factor-a (TNF-a).3 In this study, we have evaluated the ability of di erent cationic lipids to reduce footpad in¯ammation induced by carrageenan and by sheep red blood cell challenge. 4 Parenteral (i.p. or s.c) or local injection of the positively charged lipids dimethyldioctadecylammomium bromide (DDAB), dioleyoltrimethylammonium propane (DOTAP), dimyristoyltrimethylammonium propane (DMTAP) or dimethylaminoethanecarbamoyl cholesterol (DC-Chol) signi®cantly reduced the in¯ammation observed in both models in a dose-dependent manner (maximum inhibition: 70 ± 95%). 5 Cationic lipids associated with dioleyol-or dipalmitoyl-phosphatidylethanolamine retained their antiin¯ammatory activity while cationic lipids associated with dipalmitoylphosphatidylcholine (DPPC) or dimyristoylphosphatidylglycerol (DMPG) showed no anti-in¯ammatory activity, indicating that the release of cationic lipids into the macrophage cytoplasm is a necessary step for anti-in¯ammatory activity. The anti-in¯ammatory activity of cationic lipids was abrogated by the addition of dipalmitoylphosphatidylethanolamine-poly(ethylene)glycol-2000 (DPPE-PEG 2000 ) which blocks the interaction of cationic lipids with macrophages. 6 Because of the signi®cant role of protein kinase C (PKC) in the in¯ammatory process we have determined whether the cationic lipids used in this study inhibit PKC activity. The cationic lipids signi®cantly inhibited the activity of PKC but not the activity of a non-related protein kinase, PKA. The synthesis of interleukin-6 (IL-6), which is not dependent on PKC activity for its induction in macrophages, was not modi®ed in vitro or in situ by cationic lipids. The synthesis of NO and TNF-a in macrophages, both of which are PKC-dependent, was downregulated by cationic lipids. 7 These results demonstrate that cationic lipids can be considered as novel anti-in¯ammatory agents. The downregulation of pro-in¯ammatory mediators through interaction of cationic lipids with the PKC pathway may explain this anti-in¯ammatory activity. Furthermore, since cationic lipids have intrinsic anti-in¯ammatory activity, cationic liposomes should be used with caution to deliver nucleic acids for gene therapy in vivo.

Amelioration of established collagen induced arthritis by systemic IL-10 gene delivery

“…The reason for the initial drop in disease activity in the control group Gene Therapy of mice given vector plasmid is uncertain. It may be related to an effect on macrophage function of the liposomes themselves since DC-Chol-containing liposomes can reduce inflammation by interfering with macrophage nitric oxide and TNF production 59 or toxicity of that particular preparation of liposome-DNA complexes. However, the effect of transfection with IL-10 expression plasmid was over and above this non-specific effect and the reduction in disease was sustained.…”

Biodistribution and Feasibility of Non-Viral IGF-I Gene Transfers in Thermally Injured Skin

“…Amphiphiles, such as lecithin, form spherical structures in which the polar heads protect the nonpolar interior against rapid degradation. The nonviral composition, lack of cytotoxicity, increased infectivity, and anti-inflammatory properties have made the use of cholesterol-containing cationic liposomes an attractive approach for dermal gene therapy and for ameliorating the burn-induced hypermetabolic response (Filion and Philips, 1997;Jeschke et al, 1999). The mechanisms of gene transfer, biodistribution properties, systemic organ transfection or deposition, cellular uptake mechanisms, and whether the translated protein is biologically effective in the skin has not been studied in detail.…”

Activation of host antitumoral responses by cationic lipid/DNA complexes

“…This may reflect differences in the physical structure of the three cationic lipids. Filion and Phillips 10 have demonstrated that DOTAP can suppress NO production and TNF-␣ secretion from activated macrophages. It was suggested that DOTAP may suppress activated macrophages by inhibiting protein kinase C. Because DOTAP has a glycerol backbone and is structurally similar to the natural ligand for protein kinase C, diacylglycerol, it may represent a more effective inhibitor of protein kinase C function than DOTMA or DODAC, thereby leading to a more rapid resolution of lipoplex-induced inflammation.…”

“…10 Those studies demonstrated that parenteral treatment with a variety of structurally distinct cationic lipids could suppress the inflammation induced by a footpad injection of carageenan or sheep red blood cells in sensitized mice. In addition, i.p.…”

“…injection of cationic liposomes can suppress inflammation in experimental mouse models. 10 The studies described herein compared the transfection and inflammatory profiles of three different cationic lipoplex formulations containing N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N-(1- [2,3-dioleoyloxy]propyl)-N,N,N-trimethylammonium chloride (DOTAP), or N- (1-[2,3-dioleyloxy]propyl)-N,N,N-trimethylammonium chloride (DOTMA). We determined that all three formulations produce inflammation after i.p.…”