title: Kaposi's sarcoma-associated herpesvirus infection of endothelial cells inhibits neutrophil recruitment through an interleukin-6-dependent mechanism: a new paradigm for viral immune evasion.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an endothelial cell (EC) neoplasm characterized by dysregulated angiogenesis and inflammation. KSHV infection of EC causes production of proinflammatory mediators, regarded as possible initiators of the substantial mononuclear leukocyte recruitment seen in KS. Conversely, KSHV immune evasion strategies exist, such as degradation of EC leukocyte adhesion receptors by viral proteins. Here, we report the effects of KSHV infection of primary EC on recruitment of flowing leukocytes. Infection did not initiate adhesion of any leukocyte subset per se. However, on cytokine-stimulated EC, KSHV specifically inhibited neutrophil, but not PBL or monocyte, transmigration, an observation consistent with the inflammatory cell profile found in KS lesions in vivo. This inhibition could be recapitulated on uninfected EC using supernatant from infected cultures. These supernatants contained elevated levels of human interleukin 6 (hIL-6), and both the KSHV- and the supernatant-induced inhibitions of neutrophil transmigration were abrogated in the presence of a hIL-6 neutralizing antibody. Furthermore, preconditioning of EC with hIL-6 mimicked the effect of KSHV. Using RNA interference (RNAi), we show that upregulation of suppressor of cytokine signaling 3 (SOCS3) was necessary for this effect of hIL-6. These studies reveal a novel paracrine mode of KSHV immune evasion, resulting in reduced recruitment of neutrophils, a cell type whose antiviral and antitumor roles are becoming increasingly appreciated. Moreover, the findings have implications for our understanding of the contribution of hIL-6 to the pathogenesis of other inflammatory disorders and tumors in which this cytokine is abundant.
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. Lynn.Butler@ki.se
authors.forename: L M
authors.initials: LM
authors.lastname: Butler
authors.forename: H C
authors.initials: HC
authors.lastname: Jeffery
authors.forename: R L
authors.initials: RL
authors.lastname: Wheat
authors.forename: P C
authors.initials: PC
authors.lastname: Rae
authors.forename: K
authors.initials: K
authors.lastname: Townsend
authors.forename: K R
authors.initials: KR
authors.lastname: Alkharsah
authors.forename: T F
authors.initials: TF
authors.lastname: Schulz
authors.forename: G B
authors.initials: GB
authors.lastname: Nash
authors.forename: D J
authors.initials: DJ
authors.lastname: Blackbourn
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000821:virology*; D005434:Flow Cytometry; D015654:Herpesvirus 6, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000821:virology*; D019139:Tumor Escape
chemical_list: D015850:Interleukin-6