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

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).