title: FcgammaR cross-linking mediates NF-kappaB activation, reduced antigen presentation capacity, and decreased IL-12 production in monocytes without modulation of myeloid dendritic cell development.
abstract: Stimulation of monocytes (MO) through receptors for the Fc region of immunoglobulin G (FcgammaR) activates a variety of responses, including phagocytosis, antibody (Ab)-dependent cellular cytotoxicity, and production of cytokines. We previously reported that the MO subpopulation that expresses FcgammaR in high density produces high levels of tumor necrosis factor alpha (TNF-alpha) compared with FcgammaR-negative MO. Here, we show that cross-linking MO via FcgammaRI or FcgammaRII but not via FcgammaRIII activates nuclear regulatory factor-kappaB (NF-kappaB), a transcription factor involved in regulation of TNF-alpha. NF-kappaB activation peaked at 2.75 h after FcgammaRI cross-linking, involved p65 and p50 (heterodimer) and not c-rel-containing NF-kappaB complexes, and was mediated via IkappaB degradation. Cross-linking FcgammaRI, -II, as well as -III inhibited interleukin (IL)-12 (p70) production in MO, whether stimulated with Staphylococcal enterotoxin B (P<0.02) or lipopolysaccharide (P<0.02). Inhibition of IL-12 by FcgammaR cross-linking was not mediated by TNF-alpha, as the presence of an anti-TNF-alpha Ab could not restore the reduced IL-12 production. Decreased IL-12 production correlated with reduced antigen presentation capacity (P<0.01) in the FcgammaR-cross-linked MO. Blood MO can give rise to myeloid dendritic cells (DC). FcgammaR cross-linking did not modulate in vitro maturation of MO to fully functional myeloid DC. Allostimulatory capacity in mixed leukocyte reaction and DC marker expression (CDla, CD80, CD86) was not different between control and FcgammaRI cross-linked DC. These results suggest that signals mediated via FcgammaRI, -II, and -III have overlapping yet distinct effects on MO, which are likely to be involved in the fine-tuning of the immune responses to various stimuli.
authors.affiliation: Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Drechsler
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Chavan
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000328:Adult; D017951:Antigen Presentation / Q000276:immunology*; D002454:Cell Differentiation; D003432:Cross-Linking Reagents; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D052002:NF-kappa B p50 Subunit; D017452:Receptors, IgG / Q000276:immunology*; D013997:Time Factors; D051996:Transcription Factor RelA
chemical_list: D003432:Cross-Linking Reagents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D017452:Receptors, IgG; D051996:Transcription Factor RelA; D018664:Interleukin-12