INVOLVEMENT OF THE IL-2 RECEPTOR GAMMA-CHAIN (GAMMA(C)) IN THE CONTROL BY IL-4 OF HUMAN MONOCYTE AND MACROPHAGE PROINFLAMMATORY MEDIATOR PRODUCTION

IL-4 has potent anti-inflammatory properties on monocytes and suppress es both IL-1 beta and TNF-alpha production, Well-characterized compone nts 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 s ignaling from the receptor, However, mRNA levels for gamma(c) were ver y low in 7-day-cultured monocytes. As mRNA levels for gamma(c) decline d with culture, so too did the ability of IL-4 to down-regulate LPS-in duced TNF-alpha production. In contrast, IL-4 consistently down-regula ted IL-1 beta production by cultured monocytes, Immunoprecipitation an d 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 t o gamma(c) and an IL-4 mutant that is unable to bind to gamma(c) showe d 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 gamm a(c), IL-4 also suppressed IL-1 beta but not TNF-alpha production by M ono Mac 6 cells, which express minimal levels of gamma(c). For gamma(c )-expressing LPS/PMA-activated U937 cells, IL-4 decreased both TNF-alp ha and IL-1 beta production, These results suggest that functional gam ma(c) is not present on in vitro-derived macrophages, and that while s ome anti-inflammatory responses to IL-4 are lost with this down-regula tion of functional gamma(c), others are retained, We conclude that dif ferent functional responses to IL-4 by human monocytes and macrophages are regulated by different IL-4 receptor configurations.