A CD18-dependent protein kinase C beta-mediated alternative cell death pathway of activated monocytes

Abstract

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.

Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men

“…For APCs, it has recently been established that MHC class II can associate with other cell receptors. For instance in B cells, MHC class II molecules associate with CD79a/CD79b, CD20, and CD19, and in monocytes, a CD18/MHC class II complex has been identified [58,[67][68][69][70]. Which molecules associate and transduce the MHC class II-mediated signaling in activated T cells remains to be investigated, however.…”

Selective activation of specific PKC isoforms dictating the fate of CD14+ monocytes towards differentiation or apoptosis

“…Similarly, the activation of PKC-b 1 /b 2 was reported to induce the HLA-DR-mediated apoptotic cell death of THP-1 monocytic cells (Castaigne et al, 2002). This PKC-b 1 /b 2 -dependent HLA-DRmediated THP-1 cell apoptosis resulted from the activation of intrinsic caspase-dependent apoptotic signaling, and was independent of extrinsic (receptor-dependent) caspase-8-mediated apoptotic signaling (Castaigne et al, 2002). This study demonstrated that the treatment of the CD14 þ monocytes with H-PMA triggered the mitochondrial translocation of PKC-b 2 .…”

“…The treatment with 50 nM PMA was found to induce the apoptosis of human U-937 monocytic cells through eliciting PKC-b 2 -and intrinsic (mitochondria-dependent) caspasedependent apoptotic signaling (Ito et al, 2001). Similarly, the activation of PKC-b 1 /b 2 was reported to induce the HLA-DR-mediated apoptotic cell death of THP-1 monocytic cells (Castaigne et al, 2002). This PKC-b 1 /b 2 -dependent HLA-DRmediated THP-1 cell apoptosis resulted from the activation of intrinsic caspase-dependent apoptotic signaling, and was independent of extrinsic (receptor-dependent) caspase-8-mediated apoptotic signaling (Castaigne et al, 2002).…”

The superantigen staphylococcal enterotoxin A (SEA) and monoclonal antibody L243 share a common epitope but differ in their ability to induce apoptosis via MHC-II

“…Several functional effects have been reported in response to the crosslinking of MHC-II molecules such as homotypic aggregation of the cells (Mourad et al, 1990;Fuleihan et al, 1992;Kansas et al, 1992;Lehner et al, 2003), cytokine production (Homfeld et al, 1990;Mourad et al, 1992;Altomonte et al, 1993;al Daccak et al, 1994;Mehindate et al, 1994aMehindate et al, , b, 1995Rink et al, 1994;Trede et al, 1995;Bernatchez et al, 1997;Coral et al, 1997;Lei et al, 2001;Lehner et al, 2003;Meguro et al, 2003), upregulation of CD80 (Koulova et al, 1991), proliferation (Cambier et al, 1987;Lei et al, 2001, reviewed in Scholl andGeha, 1994;al Daccak et al, 2004), and also apoptosis (Truman et al, 1994;Thibeault et al, 1999;Bertho et al, 2002;Castaigne et al, 2002;Bains et al, 2003).…”

“…This is a possible explanation for another obstacle in MHC-II signal transduction research: The results of MHC-II crosslinking depend not only on the MHC-II carrying cell type used (Guo et al, 1999), but also on its maturation and/or activation state (Coral et al, 1997;Lehner et al, 2003). For example, most apoptotic influences of anti-HLA-DR antibodies are strongly enhanced only in activated or mature cells if it is detected at all (Truman et al, 1994;Bertho et al, 2002;Castaigne et al, 2002). This is understandable considering that cells of different maturation and activation states express varying surface molecules that may in each case serve as accessory proteins for MHC-II.…”