Signalling defect in FMLP-induced neutrophil respiratory burst in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are clonal haematological disorders and MDS neutrophils have various abnormal functions which cause an increased risk of infective mortality. We examined luminol-dependent chemiluminescence and cytoplasmic Ca2+ increase in order to characterize the mechanisms of a signalling defect in MDS neutrophil respiratory burst. In MDS patients, chemiluminescence stimulated with N-formyl-L-methionyl-L-leucil-L-phenylalanine (FMLP) and calcium ionophore A23187 was defective (17.2 +/- 13.7 v 44.3 +/- 16.6, P = 0.001; 42.2 +/- 21.3 v 82.0 +/- 23.6, P < 0.05, respectively), but phorbol 12-myristate 13-acetate (PMA) chemiluminescence was normal (73.4 +/- 26.9 v 79.5 +/- 23.8, P = 0.52). There were no statistical significances in cytoplasmic Ca2+ increase stimulated with FMLP and recombinant human interleukin-8 (rhIL-8) compared with controls (251.1 +/- 104.3 v 272.7 +/- 41.2, P = 0.295; 238.6 +/- 65.0 v 253.9 +/- 38.3, P = 0.567, respectively). Flow cytometric analysis of MDS neutrophils disclosed that most MDS patients showed normal neutrophil cytoplasmic Ca2+ response to FMLP and rhIL-8. However, two patients with refractory anaemia with excess of blasts displayed a significant decrease of both chemiluminescence and cytoplasmic Ca2+ response to FMLP, and they also displayed low expression of FMLP receptor. These data suggest that most MDS patients have low FMLP chemiluminescence which is not due to a defect in the FMLP receptor. It is proposed that defective FMLP chemiluminescence in MDS results from a putative defect in protein kinase C- and Ca(2+)-independent cell-signalling mechanisms. Only a small group of patients have numerical or structural defects in the FMLP receptor, causing significant decrease of neutrophil respiratory burst.
Nakaseko
C
C
Second Department of Internal Medicine, Chiba University, School of Medicine, Japan.
Asai
T
T
Wakita
H
H
Oh
H
H
Saito
Y
Y
D002118:Calcium / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D008163:Luminescent Measurements; D009190:Myelodysplastic Syndromes / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000378:metabolism*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D016897:Respiratory Burst
D016209:Interleukin-8; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium