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Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas.
J Natl Cancer Inst. 2004 Nov 17; 96(22):1691-702.JNCI

Abstract

BACKGROUND

Patients with rheumatoid arthritis or polymyositis treated with methotrexate (MTX) develop Epstein-Barr virus (EBV)-positive lymphomas more frequently than patients treated with other, equally immunosuppressive regimens. Here we determined whether MTX, in contrast to other commonly used medications for rheumatoid arthritis or polymyositis, is unique in its ability to induce the release of infectious EBV from latently infected cells.

METHODS

The effect of MTX and other immunosuppressant drugs on EBV replication in vitro was assessed using latently infected EBV-positive lymphoblastoid and gastric carcinoma cell lines. Inhibitors of signal transduction pathways were used to define requirements for induction of lytic infection. Drug effects on transcription of the two EBV immediate-early promoters (BRLF1 and BZLF1) and on promoter constructs lacking cis-acting sequences required for activation by other effectors was examined using reporter gene assays. EBV viral load in rheumatoid arthritis and polymyositis patients receiving MTX was compared with that in patients receiving other immunosuppressive medications. Statistical tests were two-sided.

RESULTS

MTX activated the release of infectious EBV from latently infected cell lines in vitro, and MTX treatment was associated with activation of the two viral immediate-early promoters in reporter gene assays. Induction of lytic EBV infection by MTX required the p38 MAP kinase, PI3 kinase, and MEK pathways and specific cis-acting motifs in the two viral immediate-early promoters. Patients treated with MTX-containing regimens had statistically significantly higher mean EBV loads in their blood than patients treated with immunosuppressing regimens that did not include MTX (40 EBV copies per 10(6) cellular genomes versus 5.1 copies; geometric mean fold difference in copies = 10.8, 95%, confidence interval = 3.0 to 38; P = .011).

CONCLUSION

MTX may promote EBV-positive lymphomas in rheumatoid arthritis and polymyositis patients by its immunosuppressive properties as well as by reactivating latent EBV.

Authors+Show Affiliations

Department of Medicine and Microbiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill 27599-7295, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15547182

Citation

Feng, Wen-hai, et al. "Reactivation of Latent Epstein-Barr Virus By Methotrexate: a Potential Contributor to Methotrexate-associated Lymphomas." Journal of the National Cancer Institute, vol. 96, no. 22, 2004, pp. 1691-702.
Feng WH, Cohen JI, Fischer S, et al. Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst. 2004;96(22):1691-702.
Feng, W. H., Cohen, J. I., Fischer, S., Li, L., Sneller, M., Goldbach-Mansky, R., Raab-Traub, N., Delecluse, H. J., & Kenney, S. C. (2004). Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. Journal of the National Cancer Institute, 96(22), 1691-702.
Feng WH, et al. Reactivation of Latent Epstein-Barr Virus By Methotrexate: a Potential Contributor to Methotrexate-associated Lymphomas. J Natl Cancer Inst. 2004 Nov 17;96(22):1691-702. PubMed PMID: 15547182.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. AU - Feng,Wen-hai, AU - Cohen,Jeffrey I, AU - Fischer,Steven, AU - Li,Li, AU - Sneller,Michael, AU - Goldbach-Mansky,Raphael, AU - Raab-Traub,Nancy, AU - Delecluse,Henri-Jacques, AU - Kenney,Shannon C, PY - 2004/11/18/pubmed PY - 2004/12/16/medline PY - 2004/11/18/entrez SP - 1691 EP - 702 JF - Journal of the National Cancer Institute JO - J Natl Cancer Inst VL - 96 IS - 22 N2 - BACKGROUND: Patients with rheumatoid arthritis or polymyositis treated with methotrexate (MTX) develop Epstein-Barr virus (EBV)-positive lymphomas more frequently than patients treated with other, equally immunosuppressive regimens. Here we determined whether MTX, in contrast to other commonly used medications for rheumatoid arthritis or polymyositis, is unique in its ability to induce the release of infectious EBV from latently infected cells. METHODS: The effect of MTX and other immunosuppressant drugs on EBV replication in vitro was assessed using latently infected EBV-positive lymphoblastoid and gastric carcinoma cell lines. Inhibitors of signal transduction pathways were used to define requirements for induction of lytic infection. Drug effects on transcription of the two EBV immediate-early promoters (BRLF1 and BZLF1) and on promoter constructs lacking cis-acting sequences required for activation by other effectors was examined using reporter gene assays. EBV viral load in rheumatoid arthritis and polymyositis patients receiving MTX was compared with that in patients receiving other immunosuppressive medications. Statistical tests were two-sided. RESULTS: MTX activated the release of infectious EBV from latently infected cell lines in vitro, and MTX treatment was associated with activation of the two viral immediate-early promoters in reporter gene assays. Induction of lytic EBV infection by MTX required the p38 MAP kinase, PI3 kinase, and MEK pathways and specific cis-acting motifs in the two viral immediate-early promoters. Patients treated with MTX-containing regimens had statistically significantly higher mean EBV loads in their blood than patients treated with immunosuppressing regimens that did not include MTX (40 EBV copies per 10(6) cellular genomes versus 5.1 copies; geometric mean fold difference in copies = 10.8, 95%, confidence interval = 3.0 to 38; P = .011). CONCLUSION: MTX may promote EBV-positive lymphomas in rheumatoid arthritis and polymyositis patients by its immunosuppressive properties as well as by reactivating latent EBV. SN - 1460-2105 UR - https://www.unboundmedicine.com/medline/citation/15547182/Reactivation_of_latent_Epstein_Barr_virus_by_methotrexate:_a_potential_contributor_to_methotrexate_associated_lymphomas_ L2 - https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djh313 DB - PRIME DP - Unbound Medicine ER -