Bacterial Lipopeptides Induce Nitric Oxide Synthase and Promote Apoptosis through Nitric Oxide-independent Pathways in Rat Macrophages (*)

Stimulation of resident peritoneal macrophages with S-[2,3-bis(pamitoyloxy)-(2R,2S)-propyl]-N-palmytoyl-(R)-CysSerLys4 or S-[2,3-bis(pamitoyloxy)-(2R,2S)-propyl]-N-palmytoyl-(R)-CysAlaLys4, two synthetic bacterial lipopeptides, promoted the expression of the inducible form of nitric oxide synthase, exhibiting a temporal pattern of nitric oxide release that was delayed with respect to the induction elicited by bacterial lipopolysaccharide. Treatment of macrophages with genistein blocked the nitric oxide synthesis triggered by the lipopeptides or lipopolysaccharide. Simultaneous incubation with lipopolysaccharide and lipopeptide resulted in an antagonistic effect on nitric oxide synthase mRNA levels and on nitrite plus nitrate release to the medium. Triggering with bacterial lipopeptides induced macrophage programmed cell death. In macrophages activated with lipopeptide, apoptosis was observed even in the absence of nitric oxide synthesis, therefore indicating the existence of alternative pathways in the control of programmed cell death in these cells.

[1]  W. Bessler,et al.  Synthetic lipopeptides as novel adjuvants. , 1992, Research in immunology.

[2]  S. Moncada.  The 1991 Ulf von Euler Lecture. The L-arginine: nitric oxide pathway. , 1992, Acta physiologica Scandinavica.

[3]  L. Boscá,et al.  Phorbol esters induce nitric oxide synthase and increase arginine influx in cultured peritoneal macrophages , 1993, FEBS letters.

[4]  J. Albina,et al.  Nitric oxide-mediated apoptosis in murine peritoneal macrophages. , 1993, Journal of immunology.

[5]  M. Marletta,et al.  Nitric oxide synthase structure and mechanism. , 1993, The Journal of biological chemistry.

[6]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[7]  G. Storz,et al.  Transcriptional regulator of oxidative stress-inducible genes: direct activation by oxidation. , 1990, Science.

[8]  Terry D. Lee,et al.  Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. , 1992, Science.

[9]  C. Hsieh,et al.  Mechanisms of lysis by cytotoxic T lymphocyte clones. Lytic activity and gene expression in cloned antigen-specific CD4+ and CD8+ T lymphocytes. , 1991, Journal of immunology.

[10]  C. Nathan,et al.  Enzymatic basis of macrophage activation. Kinetic analysis of superoxide production in lysates of resident and activated mouse peritoneal macrophages and granulocytes. , 1984, The Journal of biological chemistry.

[11]  F. Murad,et al.  Regulation and subcellular location of nitrogen oxide synthases in RAW264.7 macrophages. , 1992, Molecular pharmacology.

[12]  I. Fidler,et al.  Tyrosine phosphorylation of mitogen-activated protein kinases is necessary for activation of murine macrophages by natural and synthetic bacterial products , 1993, The Journal of experimental medicine.

[13]  W. Bessler,et al.  Synthetic lipopeptide analogs of bacterial lipoprotein are potent polyclonal activators for murine B lymphocytes. , 1985, Journal of immunology.

[14]  I. Fidler,et al.  Protein tyrosine kinase inhibitors decrease induction of nitric oxide synthase activity in lipopolysaccharide-responsive and lipopolysaccharide-nonresponsive murine macrophages. , 1993, Journal of immunology.

[15]  V. Souvannavong,et al.  Nitric oxide synthase induces macrophage death by apoptosis. , 1993, Biochemical and biophysical research communications.

[16]  W. Bessler,et al.  Rapid alterations in the plasma membrane structure of macrophages stimulated with bacterial lipopeptides. , 1992, European journal of cell biology.

[17]  B. Richardson,et al.  Evidence that macrophages are programmed to die after activating autologous, cloned, antigen‐specific, CD4+ T cells , 1993, European journal of immunology.

[18]  T. Folks,et al.  HIV gene expression enhances T cell susceptibility to hydrogen peroxide-induced apoptosis. , 1993, AIDS research and human retroviruses.

[19]  C. Nathan,et al.  Nitric oxide as a secretory product of mammalian cells , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  R. Seifert,et al.  Lipopeptides activate Gi-proteins in dibutyryl cyclic AMP-differentiated HL-60 cells. , 1993, The Biochemical journal.

[21]  C. Lowenstein,et al.  Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Nathan,et al.  Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. , 1988, Journal of immunology.