IFN-γ Alters the Response of Borrelia burgdorferi -Activated Endothelium to Favor Chronic Inflammation

Abstract

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-γ in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. Therefore, the effect of IFN-γ on the gene expression profile of primary human endothelial cells exposed to B. burgdorferi was determined. B. burgdorferi and IFN-γ 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-1β, TNF-α, and LPS also cooperated with IFN-γ to induce synergistic production of CXCL10 by the endothelium, indicating that IFN-γ 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-γ, as compared with unstimulated endothelial monolayers. In contrast, addition of IFN-γ diminished the migration of neutrophils across the B. burgdorferi-activated endothelium. IFN-γ 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.