In vivo priming of FcalphaR functioning on eosinophils of allergic asthmatics.
Inflammation in allergic asthma is characterized by an influx of eosinophils and the presence of eosinophil products in the bronchial tissue. Orchestration of this inflammatory response is in part mediated by cytokines and chemoattractants, but final activation can require additional stimuli. IgA, the most abundant immunoglobulin at mucosal surfaces, is potentially a potent trigger for eosinophil activation. Previously, we have shown that binding IgA-coated targets is dependent on in vitro stimulation of cells with cytokines. Here, we demonstrate that eosinophils isolated from the blood of allergic asthmatic patients bind IgA beads independently of prior in vitro stimulation. Furthermore, we found that the proinflammatory cytokine, TNF-alpha, is a potent enhancer of IgA binding to eosinophils from allergic asthmatics, and it does not activate FcalphaR on eosinophils isolated from normal donors. The difference in IgA binding by FcalphaRs on normal and patient eosinophils might be explained by the activation of different signal transduction pathways. Studying intracellular signaling, we found an enhanced basal activity of phosphatidylinositol 3-kinase (PI3K) in eosinophils derived from allergic asthmatics. Moreover, inhibition of PI3K in these cells blocked the background and the TNF-alpha-induced IgA binding completely. In summary, these data demonstrate that the responsiveness of human eosinophils to TNF-alpha might be an important contribution for fine-tuning the allergic inflammatory reaction. Furthermore, the preactivation of PI3K results in a broader sensitivity to subsequent challenge with inflammatory cytokines.
Bracke
M
M
Department of Pulmonary Diseases, University Medical Center, Utrecht, The Netherlands.
van de Graaf
E
E
Lammers
J W
JW
Coffer
P J
PJ
Koenderman
L
L
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D001249:Asthma / Q000097:blood* / Q000276:immunology; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007070:Immunoglobulin A / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007070:Immunoglobulin A; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011961:Receptors, Fc; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C036832:Fc(alpha) receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580