Am. J. Respir. Cell Mol. Biol.,
Volume 26, Number 3, March, 2002 315-332
Effect of IgA on Respiratory Burst and Cytokine Release by Human
Alveolar Macrophages
Role of ERK1/2 Mitogen-Activated Protein Kinases and NF- B
Youssef
Ouadrhiri,
Charles
Pilette,
Renato C.
Monteiro,
Jean-Pierre
Vaerman,
and
Yves
Sibille
Experimental Medicine Unit, Christian de Duve Institute of Cellular Pathology, University of Louvain, Brussels, Belgium; and
INSERM U25, Necker Hospital, Paris, France
Human alveolar macrophages (HAM) express Fc R receptors
for immunoglobulin (Ig)A which could link humoral and cellular branches of lung immunity. Here, we investigate the effects of polymeric (p-IgA) and secretory (S-IgA) IgA interaction
with FcR on lipopolysaccharide (LPS)- and phorbol myristate
acetate (PMA)-activated respiratory burst and TNF- release
by HAM. Activation of HAM with LPS and PMA increases the
respiratory burst and TNF- release through activation of the
extracellular signal-related protein kinases 1 and 2 (ERK1/2)
pathway, because these effects are inhibited by treatment of
HAM with PD98059, a selective inhibitor of mitogen-activated protein (MAP)/ERK kinases (MEK) pathway. S-IgA and p-IgA
downregulate the LPS-increased respiratory burst in HAM
through an inhibition of ERK1/2 activity. In contrast, p- and S-IgA
induce an increase in the respiratory burst of PMA-treated
HAM. This effect is associated with an upregulation by IgA of
the PMA-induced phosphorylation of ERK1/2 and is also inhibited by PD98059. Moreover, p-IgA and S-IgA enhance TNF-
release by HAM through an alternative pathway distinct from
ERK1/2. Because LPS is known to activate nuclear factor-B
(NF-B) in HAM, we evaluate the effect of IgA on NF-B. Treatment of HAM with LPS, p- and S-IgA, but not PMA, induces NF-B
activation through IB phosphorylation and subsequent proteolysis. Antioxidants, namely N-acetylcysteine (NAC) and glutathione (GSH), have no effects on IgA-mediated NF-B nuclear
translocation and only a minor and late effect on that of LPS, suggesting that reactive oxygen intermediates (ROI) play a minor
role in HAM activation through NF-B. TNF- release by LPS-activated HAM is sensitive to NF-B inhibition and only partly
to oxidant scavenging. In contrast, TNF- release by IgA-treated
HAM is not dependent on oxidants and only partly dependent
on NF-B. Our results show a differential HAM regulation by IgA
through both dependent and independent modulation of ERK
pathway. In addition, IgA activates NF-B and this effect was
independent on oxidants. These data may help to understand
the role of IgA in both lung protection and inflammation.
Abbreviations: antibody(ies), Ab(s); bovine serum albumin, BSA; dichlorofluorescein, DCF; electrohoretic mobility shift assay, EMSA; extracellular protein-related kinase 1 and 2, ERK 1/2; Fc high affinity receptor for
IgA, FcR; fetal calf serum, FCS; flow cytometric analysis, FCA; fluorescein isothiocyanate, FITC; glutathione, GSH; human alveolar macrophages,
HAM; horseradish peroxidase, HRP; immunoglobulin, Ig; lipopolysaccharide, LPS; monoclonal Ab, mAb; mitogen-activated protein kinase, MAP
kinase; N-acetylcysteine, NAC; nuclear factor-kappa B, NF-B; superoxide anion, O2-; optical density, OD; phospho-specific antibody cell-based
ELISA, PACE; phosphate-buffered saline, PBS; PD98059, PD; phosphorylated ERK1/2, pERK1/2; protein kinase C, PKC; phorbol myristate acetate, PMA; phenyl methyl-sulfonyl fluoride, PMSF; phosphorylated p38 MAP kinase, p-p38; respiratory burst, RB; reactive oxygen intermediates, ROI; sheep anti-mouse, SAM; SB203580, SB; swine anti-rabbit, SAR; secretory IgA, S-IgA; tris-buffered saline-tween, TBST; tumor necrosis
factor-, TNF-; WEHI 164 clone 13, WEHI.
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Copyright © 2002 American Thoracic Society.
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