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Specific Inhibition of Macrophage TNF- Expression by In Vivo Ribozyme Treatment¹

Kevin O. Kisich^2,*, Robert W. Malone^3,, Paul A. Feldstein^4, and Kent L. Erickson^5,*

Departments of ^* Cell Biology and Human Anatomy, and Medical Pathology, School of Medicine, and Department of Plant Pathology, University of California, Davis, CA 95616

The overproduction of the cytokine TNF- is associated with inflammatory and autoimmune diseases. We have developed a means to block TNF- production with ribozymes directed against TNF- mRNA to selectively inhibit its production in vitro and in vivo. Following cationic lipid-mediated delivery to peritoneal murine macrophages in culture, anti-TNF- ribozymes were more effective inhibitors of TNF- secretion than catalytically inactive ribozyme controls. Inhibition of TNF- secretion was proportional to the concentration of ribozyme administered, with an IC₅₀ of 10 nM. After i.p. injection of cationic lipid/ribozyme complexes, elicited macrophages accumulated 6% of the administered ribozyme. The catalytically active ribozyme suppressed LPS-stimulated TNF- secretion by 50% relative to an inactive ribozyme control without inhibiting secretion of another proinflammatory cytokine produced by macrophages, IL-1. Ribozyme-specific TNF- mRNA degradation products were found among the mRNA extracted from macrophages following in vivo ribozyme treatment and ex vivo stimulation. Thus, catalytic ribozymes can accumulate in appropriate target cells in vivo; once in the target cell, ribozymes can be potent inhibitors of specific gene expression.

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