The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils.
Allergic, inflammatory, and immune responses carried out by eosinophils are regulated by the cross talk between activatory and inhibitory signals. While much data has been obtained on activatory signals, inhibitory receptors on these cells have received scant attention. Therefore, we screened the surface of human peripheral blood eosinophils for inhibitory receptors using monoclonal antibodies (mAbs) previously generated to recognize receptors on human natural killer cells. Eosinophils from all of the donors examined expressed the inhibitory receptors IRp60, LIR3/ILT5, FcgammaRIIB, and p75/AIRM but not LIR1/ILT2, p58.1, p58.2, p70, or NKG2A/CD94 (n = 15). Interestingly, 25% of the donors expressed p140. IRp60 cross-linking inhibited eotaxin-dependent transmigration of eosinophils in a calcium-independent fashion. In addition, cross-linking of IRp60 on the eosinophils in the presence of IL-5/GM-CSF inhibited the antiapoptotic effect of these cytokines and blocked the release of TNF-alpha, IL-1beta, IFN-gamma, IL-4, and 3T3 fibroblast proliferation. Cross-linking of IRp60 inhibited IL-5-mediated JAK2 phosphorylation as well as eotaxin- and IL-5/GM-CSF-mediated ERK1/2 and p38 phosphorylation. Furthermore, upon cross-linking, IRp60 underwent tyrosine phosphorylation and recruited SHP-1 but not SHP-2. These findings demonstrate a novel pathway for suppressing the activity of human eosinophils, thus indicating IRp60 as a future potential target for the treatment of allergic and eosinophil-associated diseases.
Munitz
Ariel
A
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel.
Bachelet
Ido
I
Eliashar
Ron
R
Moretta
Alessandro
A
Moretta
Lorenzo
L
Levi-Schaffer
Francesca
F
D016475:3T3 Cells; D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015848:Interleukin-5 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology*; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3
D015703:Antigens, CD; C515456:CCL11 protein, human; C515070:CD300A protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D015848:Interleukin-5; C515078:KIR2DL3 protein, human; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054344:Receptors, KIR2DL3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011494:Protein Kinases