title: Autocrine and exocrine regulation of interleukin-10 production in THP-1 cells stimulated with Borrelia burgdorferi lipoproteins.
abstract: We have recently demonstrated that interleukin-10 (IL-10), produced by THP-1 monocytes in response to Borrelia burgdorferi lipoproteins, dampens the production of concomitantly elicited inflammatory cytokines. Thus, IL-10 could potentially down-regulate inflammatory and microbicidal effector mechanisms of the innate immune response to a B. burgdorferi infection, facilitating the establishment of the spirochete. To understand the mechanism(s) implicated in the regulation of the synthesis and release of IL-10 during early infection, we investigated the autocrine effects of IL-6, IL-12, tumor necrosis factor alpha (TNF-alpha), and IL-10 itself, as well as the exocrine effect of IFN-gamma on the production of macrophage-derived IL-10 with lipoprotein as a stimulant. In addition, in view of the differences in the receptor and signal transduction pathways of lipopolysaccharide (LPS) and bacterial lipoproteins, we also investigated the effects described above with LPS as a stimulant. The THP-1 human monocytic cell line and purified recombinant lipidated OspA (L-OspA) were used as the model target cell and stimulant, respectively. TNF-alpha increased the production of IL-10, as elicited by lipoproteins. The production of IL-10 by THP-1 cells stimulated with L-OspA was autoregulated by a negative feedback mechanism involving the IL-10 receptor (IL-10R). Exogenous IFN-gamma significantly inhibited the production of IL-10. Both autocrine (IL-10) and exocrine (IFN-gamma) inhibition of IL-10 production resulted in an increase in the production of the proinflammatory cytokines IL-6 and IL-12. The same results were obtained when the stimulant was LPS. The results further illustrate that IL-10 may play a pivotal role in Lyme disease pathogenesis. Moreover, the regulation of its production with lipoprotein as a stimulant is indistinguishable from that observed when LPS acts as a stimulant.
authors.affiliation: Department of Parasitology, Tulane Regional Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana 70433, USA.
authors.forename: Guillermo H
authors.initials: GH
authors.lastname: Giambartolomei
authors.forename: Vida A
authors.initials: VA
authors.lastname: Dennis
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Lasater
authors.forename: P K
authors.initials: PK
authors.lastname: Murthy
authors.forename: Mario T
authors.initials: MT
authors.lastname: Philipp
mesh_terms: D000954:Antigens, Surface / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology*; D001428:Bacterial Vaccines; D025065:Borrelia burgdorferi / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000502:physiology; D053701:Receptors, Interleukin-10
chemical_list: D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008074:Lipoproteins; C072045:OspA protein; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma