Abstract
Nitric oxide (NO) is a potent mediator involved in many biological functions including macrophage cytotoxicity and non-specific immunity against parasites, bacteria and viruses. Murine macrophages possess the capacity to express the inducible NO synthase (iNOS) which is not constitutively expressed but induced at the transcriptional level by interferon gamma (IFN-γ) alone or synergistically with LPS.
We have investigated the possible role of ADP-ribosylation reactions in the signaling pathway involved in NO synthase induction, since ADP-ribosylation has been reported to be involved in the expression of certain IFN-γ and LPS-inducible genes. We found that inhibitors of ADP-ribosylation inhibited nitrite synthesis in RAW 264.7 macrophages after stimulation by IFN-γ and LPS. These ADP-ribosylation inhibitors acted by preventing NO synthase mRNA induction, without inhibiting NO synthase enzyme activity.
IRF-1, a transcription factor induced and activated by IFN-γ was recently shown to be involved in iNOS induction. We showed that inhibitors of ADP-ribosylation had no effect on IFN-γ-mediated mRNA induction of IRF-1 nor on its activation and binding to its target sequence in the iNOS gene. In addition, the inhibitors failed to impair the IFN-γmediated antiviral activity against VSV virus. Since induction by IFN-γ of IRF-1 and induction of the antiviral state proceed through the JAK/STAT signalling pathway, our results imply that ADP-ribosylation reactions are not involved in triggering this pathway. Although the precise mechanism requires further investigation, our results indicate that ADP-ribosylation is a crucial step restricted to the signalling pathway which leads to iNOS mRNA induction, as well as TNF and MHC class II induction during macrophage activation.
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References
Schreiber, R. D., & Celada, A. 1985. Molecular characterization of IFN-γ as a macrophage activating factor. Lymphokine Res. 11: 87–118.
Trinchieri, G., & Perrussia, B. 1985. Immune interferon: A pleiotropic lymphokine with multiple effects. Immunol. Today 6: 131–136.
Stuehr, D. J., & Nathan, C. F. 1989. Nitric oxide: A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J. Exp. Med. 169: 153–1555.
Nathan, C. 1992. NO as a secretory product of mammalian cells. FASEB J. 6: 3051–3064.
Moncada, S., Palmer, R. M. J., & Higgs, E. A. 1991. Nitric oxide: Physiology, Pathophysiology and Pharmacology. Pharmacol. Rev. 43: 109–142.
Nüssler, A. K., & Billiar, T. R. 1993. Inflammation, immunoregulation and inducible nitric oxide synthase. J.Leuk.Biol. 54: 171–178.
Pellat-Deceunynck, C, Wietzerbin, J., & Drapier, J. C. 1994. Nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages. Biochem. J. 297: 53–58.
Drapier, J. C, Wietzerbin, J., & Hibbs, Jr., J. B. 1988. IFN-; and TNF-a induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. Eur. J. Immunol. 18: 1587–1592.
Deng, W., Thiel, B., Tannenbaum, C. S., Hamilton, T. A., & Stuehr, D. J. 1993. Synergistic cooperation between T cell lymphokines for induction of the nitric oxide synthase gene in murine peritoneal macrophages. J. Immunol. 151: 322–329.
Lowenstein, C. J., Alley, Z. W., Raval, P., Snowman, A. M., Snyder, S., Russell, S. W., & Murphy, W. 1993. Macrophage NOS gene: Two upstream regions mediate induction by IFN-y and LPS. Proc. Natl. Acad. Sci. USA 90: 9730–9734.
Xie, Q. W., Whisnant, R., & Nathan, C. 1993. Promoter of the mouse gene encoding calcium-independent NO synthase confers inducibility by IFN-γ and bacterial LPS. J. Exp. Med. 177: 1779–1784.
Martin, E., Nathan, C, & Xie, Q. W. 1994. Role of interferon regulatory factor-1 in induction of nitric oxide synthase. J. Exp. Med. 180: 977–984.
Kamijo, R., Harada, H., Matsuyama, T., Boslan, M., Gerecitano, T., Shapiro, D., Koh, S. I., Kimura, T., Green, S. J., Mak, T. W., Taniguchi, T., & Vilcek, J. 1994. Requirement for transcription factor IRF-1 in NOS induction in macrophages. Science 263: 1612–1617.
Kamijo, R., Shapiro, D., Le, J., Huang, S., Aguet, M., & Vilcek, J. 1993. Generation of nitric oxide and induction of major histocompatibility complex class II antigen in macrophages from mice lacking the interferon-γ receptor. Proc. Natl. Acad. Sci. USA 90: 6626–6630.
Pine, R., Canova, A., & Schindler, C. 1994. Tyrosine phosphorylated p91 binds to a single element in the ISGF-2/IRF-1 to mediate induction by IFN-α and IFN-γ, and is likely to autoregulate the p91 gene. EMBO J. 13: 158–164.
Darnell, J. E., Kerr, I. A., & Stark, G. R. 1994. JAK-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421.
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Le Page, C., Pellat-Deceunynck, C., Drapier, JC., Wietzerbin, J. (1997). Effects of Inhibitors of ADP-Ribosylation on Macrophage Activation. In: Haag, F., Koch-Nolte, F. (eds) ADP-Ribosylation in Animal Tissues. Advances in Experimental Medicine and Biology, vol 419. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8632-0_25
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DOI: https://doi.org/10.1007/978-1-4419-8632-0_25
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