Respiratory syncytial virus induces interleukin-10 by human alveolar macrophages. Suppression of early cytokine production and implications for incomplete immunity.
Respiratory syncytial virus (RSV) causes repeated infections thought to be due to an ineffective immune response. We examined the hypothesis that incomplete immunity may result, in part, from RSV-infected alveolar macrophage production of IL-10 which can interfere with the production of immunoregulatory cytokines. We also assessed whether RSV induced the expression of the 2',5' oligoadenylate (2-5A)-dependent RNase L, an endoribonuclease involved in the antiviral activities of interferons. Human alveolar macrophages were exposed to medium (uninfected control), RSV, LPS, and RSV + LPS then were assessed for expression of the cytokines TNF-alpha, IL-1 beta, IL-8, IL-10, as well as 2-5A-dependent RNase L. LPS up-regulated the expression of protein and mRNA for all cytokines. RSV stimulated the protein levels of TNF-alpha, did not alter IL-1 beta, and decreased IL-8. RSV markedly stimulated protein expression of IL-10 and 2-5A-dependent RNase L. RSV had minor effects on the steady state mRNA levels of TNF-alpha, IL-1 beta, and IL-8, yet potently induced IL-10. Cells costimulated with RSV + LPS demonstrated reduced protein and mRNA levels of TNF-alpha, IL-1 beta, IL-8 but synergistically increased IL-10 levels compared to RSV- or LPS-activated cells. Kinetic analysis indicated that RSV induced a delayed and sustained increase in IL-10 transcripts. Furthermore, RSV-infected alveolar macrophage supernatants suppressed IL-1 beta and IL-8 production by LPS-stimulated alveolar macrophages as did recombinant IL-10. Anti-IL-10 neutralized these effects. These studies indicate that RSV is capable of suppressing production of early immunoregulatory cytokines through induction of IL-10 perhaps mediated by 2-5A-dependent RNase L (or other endoribonucleases) accounting for the ineffective immune response to this virus.
Panuska
J R
JR
Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Merolla
R
R
Rebert
N A
NA
Hoffmann
S P
SP
Tsivitse
P
P
Cirino
N M
NM
Silverman
R H
RH
Rankin
J A
JA
D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000821:virology*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10