Ligation of CD11b and CD11c beta(2) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta production in primary human monocytes through a pathway dependent on nuclear factor-kappaB.
Chemokines and adhesion molecules such as integrins play a major part in the trafficking, extravasation, and recruitment of leukocytes to inflammatory sites. This study investigated the effects of beta(2) integrin engagement on chemokine production by freshly isolated human monocytes. We found that ligation of CD11b or CD11c but not CD11a alpha chains of beta(2) integrins by antibodies or soluble CD23 (sCD23) fusion proteins rapidly induced transcription and secretion of interleukin 8, macrophage inflammatory protein (MIP) 1alpha, and MIP-1beta. Because the promoters of these chemokine genes contain kappaB binding sites, we assessed the possible role of nuclear factor-kappaB (NF-kappaB) in controlling induction of the genes through beta(2) integrin engagement. Electrophoretic mobility shift assays showed that sCD23 or antibodies to CD11b or to CD11c up-regulated DNA-binding activity of NF-kappaB. Activation of NF-kappaB was accompanied by degradation of its cytosolic inhibitor IkappaB-alpha. Blockade of depletion of IkappaB-alpha by proteasome inhibitors (proteasome inhibitor I or acetyl-leucinyl-leucinyl-norleucinal) led to concomitant inhibition of NF-kappaB DNA-binding activity and expression of MIP-1alpha and MIP-1beta messenger RNA induced by beta(2) integrin ligation. These results suggest that triggering of CD11b or CD11c beta(2) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF-kappaB and subsequent secretion of MIP-1alpha and MIP-1beta that may have an important role in recruitment of other inflammatory cells during initiation of an inflammatory response.
Rezzonico
R
R
Division of Immunology and Allergy, Clinical Immunology Unit (Hans Wilsdorf Laboratory), Department of Internal Medicine, University Hospital, Geneva, Switzerland. rezzonic@unice.fr
Imbert
V
V
Chicheportiche
R
R
Dayer
J M
JM
D000906:Antibodies / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western; D018845:CD11 Antigens / Q000378:metabolism*; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003546:Cysteine Endopeptidases; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000032:analysis; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
D000906:Antibodies; D000911:Antibodies, Monoclonal; D018845:CD11 Antigens; D018821:CD18 Antigens; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D012333:RNA, Messenger; D017455:Receptors, IgE; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex