Involvement of the IL-2 Receptor γ-Chain (γc) in the Control by IL-4 of Human Monocyte and Macrophage Proinflammatory Mediator Production

Abstract

AbstractIL-4 has potent anti-inflammatory properties on monocytes and suppresses both IL-1β and TNF-α production. Well-characterized components of the IL-4 receptor on monocytes include the 140-kDa α-chain and the IL-2R γ-chain, γc, which normally dimerize 1:1 for signaling from the receptor. However, mRNA levels for γc were very low in 7-day-cultured monocytes. As mRNA levels for γc declined with culture, so too did the ability of IL-4 to down-regulate LPS-induced TNF-α production. In contrast, IL-4 consistently down-regulated IL-1β production by cultured monocytes. Immunoprecipitation and Western blot analyses demonstrated that 7-day-cultured monocytes do not express the functionally active 64-kDa γc protein. This was associated with decreased STAT6 activation by IL-4. Studies with Abs to γc and an IL-4 mutant that is unable to bind to γc showed that IL-4 can suppress IL-1β but not TNF-α production by LPS-stimulated monocytes in the presence of little or no functioning γc. IL-4 also suppressed IL-1β but not TNF-α production by Mono Mac 6 cells, which express minimal levels of γc. For γc-expressing LPS/PMA-activated U937 cells, IL-4 decreased both TNF-α and IL-1β production. These results suggest that functional γc is not present on in vitro-derived macrophages, and that while some anti-inflammatory responses to IL-4 are lost with this down-regulation of functional γc, others are retained. We conclude that different functional responses to IL-4 by human monocytes and macrophages are regulated by different IL-4 receptor configurations.