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Journal of Virology, October 1999, p. 8268-8278, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Human Herpesvirus 8 Interleukin-6 (vIL-6) Signals through gp130 but Has Structural and Receptor-Binding Properties Distinct from Those of Human IL-6

Xiaoyu Wan, Hailin Wang, and John Nicholas*

Molecular Virology Laboratories, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Received 26 March 1999/Accepted 17 June 1999

Human herpesvirus 8 (HHV-8) has been associated with classical, endemic (African), and AIDS-related Kaposi's sarcoma (KS), body cavity-based primary effusion lymphomas, and multicentric Castleman's disease (MCD). HHV-8 encodes a functional homologue of interleukin-6 (IL-6), a cytokine that promotes the growth of KS and myeloma cells and is found at elevated levels in MCD lesions and patient sera. We have previously reported that the viral IL-6 (vIL-6) gene product can support the growth of the IL-6-dependent murine hybridoma cell line, B9, and that the gp80 (IL-6 receptor [IL-6R]) component of the IL-6 receptor-signal transducer (gp180) complex plays a role in mediating this activity. However, it has been shown by others that vIL-6 can function in human cells independently of IL-6R. Here we have extended our functional studies of vIL-6 by identifying transcription factors and pathways used in human Hep3B cells, investigating the utilization of gp130 and IL-6R by vIL-6, and undertaking mutational analyses of vIL-6 and gp130. The data presented here establish that vIL-6, in common with its endogenous counterparts, can mediate signal transduction through gp130 and activate multiple transcription factors, map residues within the vIL-6 protein that are and are not important for vIL-6 signalling, and identify a gp130 mutant that is nonfunctional with respect to vIL-6 signalling in the absence of IL-6R but that retains the ability to mediate vIL-6 and human IL-6 (hIL-6) signal transduction when IL-6R is coexpressed. The data presented demonstrate functional and mechanistic similarities between vIL-6 and endogenous IL-6 proteins but also highlight differences in the structural and receptor-binding properties of vIL-6 relative to its human counterpart.

* Corresponding author. Mailing address: Molecular Virology Laboratories, Department of Oncology, Johns Hopkins University School of Medicine, 418 N. Bond St., Baltimore, MD 21231. Phone: (410) 550- 6801. Fax: (410) 550-6802. E-mail: nichojo{at}welchlink.welch.jhu.edu.

Journal of Virology, October 1999, p. 8268-8278, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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