IFN-gamma alters the response of Borrelia burgdorferi-activated endothelium to favor chronic inflammation.
Borrelia burgdorferi, the agent of Lyme disease, promotes proinflammatory changes in the endothelium that lead to the recruitment of leukocytes. The host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. Therefore, the effect of IFN-gamma on the gene expression profile of primary human endothelial cells exposed to B. burgdorferi was determined. B. burgdorferi and IFN-gamma synergistically augmented the expression of 34 genes, 7 of which encode chemokines. Six of these (CCL7, CCL8, CX3CL1, CXCL9, CXCL10, and CXCL11) attract T lymphocytes, and one (CXCL2) is specific for neutrophils. Synergistic production of the attractants for T cells was confirmed at the protein level. IL-1beta, TNF-alpha, and LPS also cooperated with IFN-gamma to induce synergistic production of CXCL10 by the endothelium, indicating that IFN-gamma potentiates inflammation in concert with a variety of mediators. An in vitro model of the blood vessel wall revealed that an increased number of human T lymphocytes traversed the endothelium exposed to B. burgdorferi and IFN-gamma, as compared with unstimulated endothelial monolayers. In contrast, addition of IFN-gamma diminished the migration of neutrophils across the B. burgdorferi-activated endothelium. IFN-gamma thus alters gene expression by endothelia exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils. This modulation may facilitate the development of chronic inflammatory lesions in Lyme disease.
Dame
Tarah M
TM
Graduate Program in Genetics, Center for Infectious Diseases, School of Medicine, Stone Brook University, Stony Brook, NY 11794, USA.
Orenzoff
Barbara L
BL
Palmer
Lance E
LE
Furie
Martha B
MB
D025065:Borrelia burgdorferi / Q000276:immunology / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D002908:Chronic Disease; D018920:Coculture Techniques; D004727:Endothelium / Q000187:drug effects* / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D007371:Interferon-gamma / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis
D018925:Chemokines; D007371:Interferon-gamma