Selective regulation of cytokine induction by adenoviral gene transfer of I kappa B alpha into human macrophages: Lipopolysaccharide-induced, but notzymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is nuclear Factor-kappa B independent

Macrophages are the major cytokine producers in chronic inflammatory diseas es, but the biochemical pathways regulating cytokine production are poorly understood. This is because genetic tools to dissect signaling pathways can not be used in macrophages because of difficulties in transfection. We have developed an adenoviral technique to achieve high efficiency gene delivery into macrophages and recently showed that spontaneous TNF-alpha production in rheumatoid arthritis joint cells, chiefly from macrophages, is 75% bloc ked by adenoviral transfer of I kappa B alpha. In this report we use the sa me adenovirus to investigate whether the production of a number of proinfla mmatory cytokines (e.g., TNF-alpha, IL-1 beta, IL-6, and IL-8) from human m acrophages depends on NF-kappa B, While the cytokine response to certain in ducers, such as LPS, PMA, and UV light, is blocked by overexpression of I k appa B alpha, the response to zymosan is not. In contrast, anti-inflammator y mediators (IL-10 and IL-1 receptor antagonist) induced by LPS are only ma rginally inhibited by I kappa B alpha excess. These studies demonstrate sev eral new points about macrophage cytokine production. First, there is heter ogeneity of mechanisms regulating both the proinflammatory and anti-inflamm atory cytokines within populations of a single cell type. In addition, the results confirm the utility of the adenoviral technique for functional anal ysis of cytokine induction. The results also confirm that there are autocri ne and paracrine interactions regulating cytokine synthesis within a single cell type. The selectivity of NF-kappa B blockade for proinflammatory but not anti-inflammatory mediators indicates that in macrophages, NF-kappa B m ay be a good target for the treatment of chronic inflammatory diseases.