title: beta-Chemokine production in CD40L-stimulated monocyte-derived macrophages requires activation of MAPK signaling pathways.
abstract: CD40 ligand is a cell surface molecule on CD4(+) T cells that interacts with its receptor, CD40, on antigen presenting cells to mediate humoral and cellular immune responses. Our previous studies demonstrated that a trimeric soluble form of CD40L (CD40LT) activates macrophages to produce beta-chemokines and decrease CCR5 and CD4 cell surface expression, thus inducing resistance to HIV-1 infection. However, the mechanism(s) by which CD40LT mediates these effects in primary macrophages remains unclear. In this report, we demonstrate that CD40LT induces synthesis of beta-chemokines through the activation of MAPK signaling pathways. Treatment of macrophages with CD40LT results in a rapid activation of p38 and ERK1/2 mitogen-activated protein kinases. Inhibitors of these MAPKs blocked beta-chemokine production, while protein kinase A and C inhibitors had little or no effect. We also provide evidence that CD40LT stimulates beta-chemokine production directly, as well as indirectly via a TNF-alpha-dependent mechanism. At the early time points, CD40LT directly stimulated beta-chemokine production, whereas at later time points the effect was mediated to some extent by TNF-alpha. In conclusion, our results suggest that CD40-CD40L interactions are important for the activation of monocyte-derived macrophage antiviral response affecting both viral replication and the recruitment of immune cells.
authors.affiliation: Department of Molecular Pathogenesis of HIV, The Picower Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA. pdimarzi@nshs.edu
authors.forename: Paola Di
authors.initials: PD
authors.lastname: Marzio
authors.forename: Barbara
authors.initials: B
authors.lastname: Sherry
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Thomas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Franchin
authors.forename: Helena
authors.initials: H
authors.lastname: Schmidtmayerova
authors.forename: Michael
authors.initials: M
authors.lastname: Bukrinsky
mesh_terms: D023201:CD40 Ligand / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019742:Chemokines, CC; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases