Stroma cell-derived factor 1alpha mediates desensitization of human neutrophil respiratory burst in synovial fluid from rheumatoid arthritic patients.
Classical chemoattractants such as fMLP or the complement factor C5a use G protein (Gi)-coupled receptors to stimulate both chemotaxis and production of reactive oxygen species (respiratory burst, RB) by polymorphonuclear leukocytes (PMN). The chemokine stroma cell-derived factor 1alpha (SDF1alpha) and its Gi-coupled receptor, CXCR4, regulate leukocyte trafficking and recruitment to the synovial fluid of rheumatoid arthritic patients (RA-SF). However, the role of SDF1alpha in the RB is unknown and was studied in this work in vitro with healthy PMN in the absence and presence of RA-SF. In healthy PMN, SDF1alpha failed to stimulate the RB, even though the p38 mitogen-activated protein kinase was activated to a similar level as in fMLP-stimulated PMN. In contrast, the SDF1alpha-mediated calcium transients and activation of phosphatidylinositol 3-kinase/Akt were partially deficient, while p44/42 mitogen-activated protein kinases were not activated. SDF1alpha actually desensitized weakly the fMLP-mediated RB of healthy PMN. This cross-inhibitory effect was amplified in PMN treated with RA-SF, providing a protection against the exacerbation of RB induced by C5a or fMLP. This SDF1alpha beneficial effect, which was prevented by the CXCR4 antagonist AMD3100, was associated with impairment of C5a- and fMLP-mediated early signaling events. Thus, although SDF1alpha promotes leukocyte emigration into rheumatoid synovium, our data suggest it cross-desensitizes the production of oxidant by primed PMN, a property that may be beneficial in the context of arthritis.
Lenoir
Monique
M
Département de Biologie Cellulaire, Institut Cochin, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Recherche Médicale Unité 567, and Université René Descartes, Paris, France.
Djerdjouri
Bahia
B
Périanin
Axel
A
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D015936:Complement C5a / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4 / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects*; D013582:Synovial Fluid / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D002118:Calcium