International Immunology, Vol. 14, No. 9, pp. 1003-1014,
September 2002
© 2002 Japanese Society for Immunology
A CD18-dependent protein kinase C ß-mediated alternative cell death pathway of activated monocytes
1 Unité INSERM U396, Institut de Recherches Biomédicales des Cordeliers, 15 rue de l’école de médicine, 75006 Paris, France and Laboratoire d‘Immunologie et d‘Histocompatibilité, Hôpital Sainte Louis AP-HP, 75475 Paris France 2 Centre de Recherche en Rhumatologie et Immunologie, CHUL, Université Laval, Québec G1V 4G2, Canada
Correspondence to: R. Al-Daccak, INSERM, U396, 15 rue de l’École de Médicine, 75006, Paris, France. E-mail: Reem.Al-Daccak{at}bhdc.jussieu.fr
Transmitting editor: S. Romagnani
Activated monocytes become resistant to numerous death stimuli including death receptors. Given that the uncontrolled activation of monocytes/macrophages and their persistence can lead to severe inflammatory conditions, it is critical to define the pathways that control their elimination. We previously reported that ligation of HLA-DR molecules on peripheral blood-derived monocytes induces their death. To investigate the mechanisms of HLA-DR-mediated death in monocytes, we used the THP-1 monocytic cell line as a model. We show that while THP-1 are equally resistant to HLA-DR- and to Fas-mediated death, treatment of THP-1 with IFN-
renders them sensitive to HLA-DR- but not to Fas-mediated death. Both activation of the Src family protein tyrosine kinase and classical protein kinase C (PKC) occur through HLA-DR, but only PKC activation is involved in HLA-DR-mediated death of these cells. Moreover, HLA-DR-mediated cell death of activated monocytes implicates a regulatory loop between the HLA-DR/CD18 complex and the downstream activation of PKCß. Thus, our study identifies an alternative physiological signaling pathway of monocyte death, and further investigation on its regulation is likely to provide significant insights into the control of monocyte homeostasis and inflammation.
Keywords: apoptosis, integrins, macrophages, MHC class II, protein tyrosine kinase, signaling