The immunomodulation of pro-inflammatory cytokines such as tumor necrosis factor-α(TNF-α) from macrophages, stimulated by plasmid DNA with CpG motifs, is a critical process for the success of gene therapy. These proinflammatory cytokines have been reported to inhibit transgene expression and induce acute toxicity in lipid-based systemic gene delivery systems. However, very little is known about inflammatory toxicity using non-lipid based gene delivery systems such as dendrimers. In the present study, pulmonary surfactant was proposed to modulate TNF-α secretion in cultured RAW 264.7 murine macrophage-like cells activated by pDNA and dendrimer-mediated transfection. We found that pulmonary surfactant suppressed TNF-α release in macrophages activated by plasmid DNA and dendrimer-mediated transfection. Also, the inhibitory effect of pulmonary surfactant followed a dose-dependent manner. Simultaneously, pulmonary surfactant enhanced transfection efficiencies mediated by dendrimers in macrophage cells. The immunologic properties of some of the individual components of naturally or synthetically pulmonary surfactant have also been investigated. 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC), 1,2-Dioleoyl-sn-Glycero-3-[Phospho-rac-(1-glycerol)] (Sodium Salt) (DOPG), and tyloxapol have minimally inhibitory effects of TNF-α release in macrophages activated by pDNA and dendrimer-mediated transfection. These findings suggest that incorporation of pulmonary surfactant into dendrimer-based gene delivery systems can offer synergistically advantage effects in anti-inflammation and transfection efficiencies.
