A CD18-dependent protein kinase C beta-mediated alternative cell death pathway of activated monocytes.
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-gamma 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 PKCbeta. 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.
Unité INSERM U396, Institut de Recherches Biomédicales des Cordeliers, 15 rue de l'école de médicine, 75006 Paris, France.
Jean-Gabriel
JG
Castaigne
Wenyan
W
Guo
Claire
C
Lévéille
Dominique
D
Charron
Reem
R
Al-Daccak
D018821:CD18 Antigens / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D006684:HLA-DR Antigens / Q000276:immunology / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000502:physiology*; D064546:Protein Kinase C beta; D015398:Signal Transduction
D018821:CD18 Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D011493:Protein Kinase C; D064546:Protein Kinase C beta