T‐Lymphocyte‐derived interferon‐γ (IFN‐γ) mediates inflammatory responses to hypercholesterolemia, but is not the primary source of elevated plasma IFN‐γ

Abstract

Hypercholesterolemia elicits an inflammatory phenotype in the microvasculature. T-lymphocytes mediate these responses via an IFN-γ dependent pathway. However it remains unclear whether plasma levels of IFN-γ are raised during hypercholesterolemia, and whether T-lymphocytes are the source of this circulating cytokine. We measured IFN-γ levels in wild-type (WT), immunodeficient (SCID) and IFN-γ deficient (IFN-γ ko) mice placed on a normal (ND) or high cholesterol diet (HC) for 2 wk and correlated these levels with microvascular inflammation. Separate SCID-HC mice received T-cells derived from WT or IFN-γ ko mice. HC led to a 5-fold increase in plasma IFN-γ levels in WT mice. This was not observed in SCID or IFN-γ ko mice. Transfer of WT T-cells to SCID mice restored IFN-γ levels to those observed in WT-HC, paralleling the microvascular inflammatory responses to HC. However SCID mice that received T-cells from IFN-γ ko mice also exhibited increased IFN-γ levels, in contrast to the abrogated microvascular inflammation in these mice. Our findings suggest that although T-lymphocyte-derived IFN-γ contributes to the microvascular responses to HC, these cells are unlikely to be the source of the accompanying rise in plasma IFN-γ. It remains unclear whether raised plasma levels of IFN-γ, perhaps from NK cells, are necessary for the IFN-γ-mediated microvascular inflammation elicited by HC. (Supported by R01 HL26441).