title: Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes.
abstract: The human cytomegalovirus (HCMV) gene UL111A encodes cytomegalovirus-encoded human interleukin-10 (cmvIL-10), a homolog of the potent immunomodulatory cytokine human interleukin 10 (hIL-10). This viral homolog exhibits a range of immunomodulatory functions, including suppression of proinflammatory cytokine production and dendritic cell (DC) maturation, as well as inhibition of major histocompatibility complex (MHC) class I and class II. Here, we present data showing that cmvIL-10 upregulates hIL-10, and we identify CD14(+)monocytes and monocyte-derived macrophages and DCs as major sources of hIL-10 secretion in response to cmvIL-10. Monocyte activation was not a prerequisite for cmvIL-10-mediated upregulation of hIL-10, which was dose dependent and controlled at the transcriptional level. Furthermore, cmvIL-10 upregulated expression of tumor progression locus 2 (TPL2), which is a regulator of the positive hIL-10 feedback loop, whereas expression of a negative regulator of the hIL-10 feedback loop, dual-specificity phosphatase 1 (DUSP1), remained unchanged. Engagement of the hIL-10 receptor (hIL-10R) by cmvIL-10 led to upregulation of heme oxygenase 1 (HO-1), an enzyme linked with suppression of inflammatory responses, and this upregulation was required for cmvIL-10-mediated upregulation of hIL-10. We also demonstrate an important role for both phosphatidylinositol 3-kinase (PI3K) and STAT3 in the upregulation of HO-1 and hIL-10 by cmvIL-10. In addition to upregulating hIL-10, cmvIL-10 could exert a direct immunomodulatory function, as demonstrated by its capacity to upregulate expression of cell surface CD163 when hIL-10 was neutralized. This study identifies a mechanistic basis for cmvIL-10 function, including the capacity of this viral cytokine to potentially amplify its immunosuppressive impact by upregulating hIL-10 expression.
  
  
  OBJECTIVE
  Human cytomegalovirus (HCMV) is a large, double-stranded DNA virus that causes significant human disease, particularly in the congenital setting and in solid-organ and hematopoietic stem cell transplant patients. A prominent feature of HCMV is the wide range of viral gene products that it encodes which function to modulate host defenses. One of these is cmvIL-10, which is a homolog of the potent immunomodulatory cytokine human interleukin 10 (hIL-10). In this study, we report that, in addition to exerting a direct biological impact, cmvIL-10 upregulates the expression of hIL-10 by primary blood-derived monocytes and that it does so by modulating existing cellular pathways. This capacity of cmvIL-10 to upregulate hIL-10 represents a mechanism by which HCMV may amplify its immunomodulatory impact during infection.
authors.affiliation: Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Selmir
authors.initials: S
authors.lastname: Avdic
authors.affiliation: Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Brian P
authors.initials: BP
authors.lastname: McSharry
authors.affiliation: Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Megan
authors.initials: M
authors.lastname: Steain
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Poole
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Sinclair
authors.affiliation: Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Allison
authors.initials: A
authors.lastname: Abendroth
authors.affiliation: Discipline of Infectious Diseases and Immunology, University of Sydney, Sydney, New South Wales, Australia barry.slobedman@sydney.edu.au.
authors.forename: Barry
authors.initials: B
authors.lastname: Slobedman
mesh_terms: D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology; D015967:Gene Expression Regulation, Viral; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C405505:IL-10 like protein, Human herpesvirus 5; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014764:Viral Proteins; D016753:Interleukin-10; D006419:Heme Oxygenase (Decyclizing); D019869:Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase