Involvement of the IL-2 receptor γ-chain (γc) in the control by IL-4 of human monocyte and macrophage proinflammatory mediator production

IL-4 has potent anti-inflammatory properties on monocytes and suppresses both IL-1 beta and TNF-alpha production, Well-characterized components of the IL-3 receptor on monocytes include the 140-kDa alpha-chain and the IL-2R gamma-chain, gamma(c), which normally dimerize 1:1 for signaling from the receptor, However, mRNA levels for gamma(c) were very low in 7-day-cultured monocytes. As mRNA levels for gamma(c) declined with culture, so too did the ability of IL-4 to down-regulate LPS-induced TNF-alpha production. In contrast, IL-4 consistently down-regulated IL-1 beta production by cultured monocytes, Immunoprecipitation and Western blot analyses demonstrated that 7-day-cultured monocytes do not express the functionally active 64-kDa gamma(c) protein, This was associated with decreased STAT6 activation by IL-4. Studies with Abs to gamma(c) and an IL-4 mutant that is unable to bind to gamma(c) showed that IL-4 can suppress IL-1 beta but not TNF-alpha production by LPS-stimulated monocytes in the presence of little or no functioning gamma(c), IL-4 also suppressed IL-1 beta but not TNF-alpha production by Mono Mac 6 cells, which express minimal levels of gamma(c). For gamma(c)-expressing LPS/PMA-activated U937 cells, IL-4 decreased both TNF-alpha and IL-1 beta production, These results suggest that functional gamma(c) 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 gamma(c), 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.