Correction to: Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response.

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Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response.

Measles virus (MV) is highly contagious pathogen, which causes a profound immunosuppression, resulting in high infant mortality. This virus infects dendritic cells (DCs) following the binding of MV hemagglutinin (MV-H) to CD150 receptor and alters DC functions by a mechanism that is not completely understood. We have analyzed the effect of MV-H interaction with CD150-expressing DCs on the DC signaling pathways and consequent phenotypic and functional changes in the absence of infectious context. We demonstrated that contact between CD150 on human DCs and MV-H expressed on membrane of transfected CHO cells was sufficient to modulate the activity of two major regulatory pathways of DC differentiation and function: to stimulate Akt and inhibit p38 MAPK phosphorylation, without concomitant ERK1/2 activation. Furthermore, interaction with MV-H decreased the expression level of DC activation markers CD80, CD83, CD86, and HLA-DR and strongly downregulated IL-12 production but did not modulate IL-10 secretion. Moreover, contact with MV-H suppressed DC-mediated T-cell alloproliferation, demonstrating profound alteration of DC maturation and functions. Finally, engagement of CD150 by MV-H in mice transgenic for human CD150 decreased inflammatory responses, showing the immunosuppressive effect of CD150-MV-H interaction in vivo. Altogether, these results uncover novel mechanism of MV-induced immunosuppression, implicating modulation of cell signaling pathways following MV-H interaction with CD150-expressing DCs and reveal anti-inflammatory effects of CD150 stimulation.

CD150 regulates JNK1/2 activation in normal and Hodgkin's lymphoma B cells.

The CD150 receptor is expressed on thymocytes, activated and memory T cells, B cells, platelets, natural killer T cells, and mature dendritic cells, and is also detected on tumor cells of Hodgkin's lymphoma (HL) and diffuse large B-cell lymphoma with an activated B cell phenotype. Here, we report that the level of CD150 expression is elevated during B cell differentiation toward plasma cells. In primary tonsillar B cells and HL cell lines, CD150 signaling regulates the phosphorylation of three types of mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and Jun N-terminal kinase 1/2 (JNK1/2). CD150 induced ERK1/2 activation in primary tonsillar B cells and in two HL cell lines. CD150 mediated activation of JNK1/2 p54 and JNK2-gamma kinase isoforms in all CD150(+) B cell lines we tested. CD150 associated with the serine/threonine kinase hematopoetic progenitor kinase 1 (HPK1) regardless of CD150 tyrosine phosphorylation or binding of the SH2D1A adaptor protein to CD150, and HPK1 overexpression enhanced CD150-mediated JNK1/2 phosphorylation. CD150 ligation inhibited cell proliferation of all studied HL cell lines and induced apoptosis in L1236 HL cells that did not depend on JNK activity. As signaling through CD150 modulates MAPK activity in HL tumor cells, CD150 may contribute to regulation of tumor cell maintenance in low-rate proliferating HLs.

Signal transduction pathways in Burkitt's lymphoma cell lines BL41 and DG75 with different sensitivity to doxorubicin.

AIM: To understand the biochemical basis of cell sensitivity to cytotoxic effect of doxorubicine (DOX), we investigated signaling cascades mediated by c-Jun N-terminal protein kinases (JNK1/2), p38 mitogen-activated protein kinases (MAPK), extracellular signal-regulated protein kinase (ERK1/2) and protein kinase B/Akt in both DOX-sensitive BL41 and the DOX-resistant DG75 Burkitt's lymphoma (BL) cell lines. METHODS: To test the effect of DOX on different signaling cascades, BL41 and DG75 cells were treated with DOX for varying lengths of time. Cytotoxic effect of DOX was analyzed by Hoechst 33342 staining. Total amount of JNK1/2, ERK1/2, p38 MARK, Akt proteins, and also phosphorylated/activated forms of these enzymes were detected using Western blot analysis with specific antibodies. Immunophenotypic analysis of BL41 and DG75 cells was performed by indirect immunofluorescence staining. RESULTS: Our findings demonstrated that DOX treatment of the BL41 cells led to sustained activation of JNK1/2 and p38 MAPK. This activation/phosphorylation did not result from increased expression of either JNK1/2 or p38 MAPK since protein levels of JNK1/2 and p38 MAPK in DOX-treated and untreated cells were unaltered. Apoptotic signaling cascade induced by DOX in BL41 cell was accompanied by Akt dephosphorylation. The effect of DOX in drug-resistant cell line DG75 convoyed by dephosphorylation of JNK1/2, p38 MAPK and activation of Akt. Fate of BL cells did not depend from ERK activity. CONCLUSION: The outcome of cellular response to DOX in BL cell lines is determined by interference of at least three signaling pathways: JNK1/2, p38 MAPK and PKB/Akt. The balance between Akt/PKB and MAPK pathways is important in determining whether BL cells survive or undergo apoptosis in response to DOX treatment.