collected clinical data. V. V. and P. M. supervised the study. V. B., V. V., K. J. M., N. K. B., O. D., P. M., and P. D. wrote the paper. This work was supported in part by the Institut National de la Recherche Médicale (INSERM), and by the Université Pierre et Marie Curie UPMC – Paris-6.
Conflict of Syk inhibitor interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“The human soluble CD23 (sCD23) protein displays highly pleiotropic cytokine-like activity. Monocytic cells express the sCD23-binding integrins αVβ3, αVβ5, αMβ2 and αXβ2, but it is unclear which of these four integrins most acutely regulates sCD23-driven cytokine release. The hypothesis that ligation of different sCD23-binding integrins promoted release of distinct subsets of cytokines was tested. Lipopolysaccharide (LPS) and sCD23 promoted release of distinct groups
of cytokines from the THP-1 model cell line. The sCD23-driven cytokine release signature was characterized by elevated amounts of RANTES (CCL5) and a striking increase in interleukin-8 (IL-8; CXCL8) secretion, but little release of macrophage inflammatory protein 1β (MIP-1β; CCL4). Antibodies to αVβ3 or αXβ2 both promoted IL-8 release, consistent with the sCD23-driven pattern, but both also evoked GSK-3 signaling pathway strong MIP-1β secretion; simultaneous ligation of these two integrins further increased cytokine secretion but did not alter the pattern of cytokine output. In both model cell lines
and primary tissue, integrin-mediated cytokine release was more pronounced in immature monocyte cells than in mature cells. The capacity of anti-integrin monoclonal antibodies to elicit a cytokine release response Ureohydrolase is epitope-dependent and also reflects the differentiation state of the cell. Although a pattern of cytokine release identical to that provoked by sCD23 could not be elicited with any individual anti-integrin monoclonal antibody, αXβ2 and αVβ3 appear to regulate IL-8 release, a hallmark feature of sCD23-driven cytokine secretion, more acutely than αMβ2 or αVβ5. Human CD23 is a 45 000 dalton molecular weight type II transmembrane glycoprotein of the C-type lectin family that expresses a range of biological activities in the membrane-bound and freely soluble forms.1–3 As a membrane protein, CD23 functions as the low-affinity receptor for IgE4 and can form cell–cell contacts with CD21,5,6 leading to homotypic adhesion of activated B lymphocytes.7,8 Data from CD23−/− mice are consistent with the interpretation that CD23 is a negative regulator of IgE synthesis by B cells.9–11 Membrane-bound CD23 is released from cells by the action of metalloproteases,12 and the family of soluble CD23 (sCD23) species released have pleiotropic cytokine-like activities.