Effect of IgA on Respiratory Burst and Cytokine Release by Human Alveolar Macrophages: Role of ERK1/2 Mitogen-Activated Protein Kinases and NF- κ B


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Abstract

Human alveolar macrophages (HAM) express Fc α 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 Fc α R on lipopolysaccharide (LPS)- and phorbol myristate acetate (PMA)-activated respiratory burst and TNF- α release by HAM. Activation of HAM with LPS and PMA increases the respiratory burst and TNF- α 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- α release by HAM through an alternative pathway distinct from ERK1/2. Because LPS is known to activate nuclear factor- κ B (NF- κ B) in HAM, we evaluate the effect of IgA on NF- κ B. Treatment of HAM with LPS, p- and S-IgA, but not PMA, induces NF- κ B activation through I κ B α phosphorylation and subsequent proteolysis. Antioxidants, namely N-acetylcysteine (NAC) and glutathione (GSH), have no effects on IgA-mediated NF- κ 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- κ B. TNF- α release by LPS-activated HAM is sensitive to NF- κ B inhibition and only partly to oxidant scavenging. In contrast, TNF- α release by IgA-treated HAM is not dependent on oxidants and only partly dependent on NF- κ B. Our results show a differential HAM regulation by IgA through both dependent and independent modulation of ERK pathway. In addition, IgA activates NF- κ B and this effect was independent on oxidants. These data may help to understand the role of IgA in both lung protection and inflammation.

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