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Endotoxin-Induced Gamma Interferon Production: Contributing Cell Types and Key Regulatory Factors

Department of Anesthesiology, The University of Texas Medical Branch,¹ The Shriner's Hospital for Children-Galveston Burns Unit, Galveston, Texas²

Received 30 July 2001/ Returned for modification 5 October 2001/ Accepted 2 January 2002

Gamma interferon (IFN-) is an important mediator of endotoxin (lipopolysaccharide [LPS])-induced immune responses. However, the specific cell types that produce IFN- in response to LPS and the cellular factors that regulate LPS-induced IFN- production have not been fully determined. The present studies were undertaken to characterize the cell populations that produce IFN- after LPS challenge in the spleens of mice and to determine the regulatory factors that modulate LPS-induced production of IFN-. Our studies show that the levels of splenic IFN- mRNA and protein production peak at 6 and 8 h, respectively, after systemic LPS challenge. Approximately 60% of IFN--producing cells are natural killer (NK) cells (CD3^-DX5⁺) and 25% are NKT cells (CD3⁺DX5⁺). Most of the remaining IFN--producing cells are T cells (CD3⁺DX5^-), macrophages, and dendritic cells. Functionally, interleukin-12 (IL-12) is the major IFN--stimulating factor after LPS challenge, with costimulation provided by IL-15, IL-18, and B7 proteins. IL-10 is a major inhibitor of LPS-induced IFN- production. Unlike intact heat-killed gram-negative and gram-positive bacteria, the class II major histocompatibility complex did not play a functional role in LPS-induced IFN- production. LPS is a potent stimulus for splenic IL-10, IL-12 p40, and IL-15 mRNA expression, whereas IL-12 p35 and IL-18 mRNAs, as well as B7 proteins, are constitutively expressed in the mouse spleen. Of the factors studied, IL-18 serves as the most potent costimulus with IL-12 for IFN- production, followed by IL-15 and B7 proteins. These data demonstrate that NK cells and NKT cells are the most abundant IFN--producing cells in the mouse spleen after LPS challenge and that IL-10 and IL-12 are key functional regulators of LPS-induced IFN- production.

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