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-Chain (c) in the Control by IL-4 of Human Monocyte and Macrophage Proinflammatory Mediator Production1
*
Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University of South Australia, Adelaide, Australia; and
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
IL-4 has potent anti-inflammatory properties on monocytes and
suppresses both IL-1ß and TNF-
production. Well-characterized
components of the IL-4 receptor on monocytes include the 140-kDa
-chain and the IL-2R 
-chain, c, which
normally dimerize 1:1 for signaling from the receptor. However, mRNA
levels for c were very low in 7-day-cultured monocytes.
As mRNA levels for c declined with culture, so too did
the ability of IL-4 to down-regulate LPS-induced TNF- production. In
contrast, IL-4 consistently down-regulated IL-1ß production by
cultured monocytes. Immunoprecipitation and Western blot analyses
demonstrated that 7-day-cultured monocytes do not express the
functionally active 64-kDa c protein. This was
associated with decreased STAT6 activation by IL-4. Studies with Abs to
c and an IL-4 mutant that is unable to bind to
c showed that IL-4 can suppress IL-1ß but not TNF-
production by LPS-stimulated monocytes in the presence of little or no
functioning c. IL-4 also suppressed IL-1ß but not
TNF- production by Mono Mac 6 cells, which express minimal levels of
c. For c-expressing LPS/PMA-activated
U937 cells, IL-4 decreased both TNF- and IL-1ß production. These
results suggest that functional 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
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.
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