Ligation of CD11b and CD11c β2 integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1α (MIP-1α) and MIP-1β production in primary human monocytes through a pathway dependent on nuclear factor–κB

Abstract

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 ␤ 2 integrin engagement on chemokine production by freshly isolated human monocytes. We found that ligation of CD11b or IntroductionRecruitment of circulating leukocytes to an inflammatory site in response to stimuli such as infectious agents (viruses, bacteria, and protozoans) or noninfectious processes (trauma, autoimmune disorders, and ischemia-reperfusion injury) is a crucial step in the development of both acute and chronic inflammatory responses. In all these conditions, extravasation of circulating leukocytes requires communication with vascular endothelial cells that in turn depends on an interrelated network of events involving the finely regulated action of inflammatory cytokines (ie, interleukin [IL] 1 and tumor necrosis factor [TNF]-␣), adhesion molecules (notably integrins), and chemoattractant cytokines called chemokines.Chemokines are highly conserved, small, secreted or membranebound cytokines with molecular masses of 6 to 14 kd and a characteristic 4-cysteine motif in their amino acid sequence. [1][2][3] Two main subfamilies are defined according to the position of the first 2 cysteine residues. In the CXC (or ␣-chemokine) subfamily, these residues are separated by one amino acid, whereas in the CC (or ␤-chemokine) subfamily, they are adjacent. The ␤-chemokines, which include monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP) 1␣, MIP-1␤, and regulated on activation, normal T-cell expressed and secreted (RANTES) molecules, are potent chemotactic agents for monocytes. 4,5 The migratory behavior of monocytes in response to a concentration gradient of these soluble chemotactic factors also depends on adhesion molecules, particularly the leukocyte-specific ␤ 2 integrins.Integrins are part of a family of heterodimeric transmembrane glycoproteins that recognize a variety of ligands or counterreceptors, including extracellular matrix and cell-surface and plasma proteins, and that consequently control numerous physiologic functions, such as adhesion, locomotion, chemotaxis, and phagocytosis. 6 Expression of ␤ 2 integrins is restricted to leukocytes, with distribution varying among leukocyte subtypes. The ␤ 2 integrins share a common ␤ chain (CD18) and have at least 4 distinct ␣ chains noncovalently associated with CD18: lymphocyte functional antigen 1 (␣ L ␤ 2 , CD11a/CD18), macrophage antigen 1 (Mac-1; ␣ M ␤ 2 , CR3, CD11b/CD18), p150,95 (␣ X ␤ 2 , CR4, CD11c/ CD18), and a newly characterized member, ␣ D ␤ 2 (CD11d/ CD18). 7-9 Interestingly, some chemokines (MCP-1, MIP-1␣, MIP-1␤, and RANTES) increase surface expression of CD11b/CD18 and CD11c/CD18 on human monocytes. [10][11][12] The best characterized ligands of CD11a/CD18 are intracellular adhesion molecule (ICAM) 1 (CD54), ICAM-2 (CD102), and ICAM-3 (CD50), all of which are members of the immunoglobulin superfamily. [13][14...

Interleukin-1 Family Member 9 Stimulates Chemokine Production and Neutrophil Influx in Mouse Lungs

“…In the present study, IL-1F9 induced NF-kB activity in macrophages and increased the mRNA expression of CXCL1 and CXCL2, two major chemokines implicated in neutrophil chemotaxis. The gene expression of chemokines such as CCL2, CCL3, CCL5, CCL7, CCL11, CXCL1, CXCL2, and CXCL5 are regulated by NF-kB (17,(35)(36)(37)(38)(39)(40)(41)(42). The transcript expression of these chemokines is also upregulated in the lungs of mice after the intratracheal instillation of IL-1F9.…”

Activation of Monocytic Cells Through Fcγ Receptors Induces the Expression of Macrophage-Inflammatory Protein (MIP)-1α, MIP-1β, and RANTES

“…These results are reminiscent of those recently reported in human monocytes. Thus, triggering of ␤ 2 integrins by both Ab and soluble CD23 has shown a strong induction of both MIP-1␣ and MIP-1␤, which was sensitive to proteasome inhibitors, whereas this treatment enhanced IL-8 expression (39). In addition, treatment of human monocytes with 15-deoxy-⌬ 12,14 PGJ 2 has been found to produce IL-8 gene expression (40), although the function of this peroxisome proliferator-activated receptor-␥ activator has been associated with an antiinflammatory effect linked to the inhibition of the NF-B route (41).…”

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…CD11b/CD18 ligation and clustering mediate proinflammatory signaling in leukocytes, including synergistic potentiation of signaling by other receptors (23)(24)(25)(26)(27)(28)(29)(30)(31). Conversely, they have also been shown to negatively regulate signaling by TLRs, TNF receptors, and cytokine receptors (14,17,23,24,(32)(33)(34), which could suppress downstream IFN-I pathways.…”