Regulation of Chemokines, CCL3 and CCL4, by Interferon γ and Nitric Oxide Synthase 2 in Mouse Macrophages and During Salmonella enterica Serovar Typhimurium Infection

Background. Interferon γ (IFN-γ) increases the expression of multiple genes and responses; however, the mechanisms by which IFN-γ downmodulates cellular responses is not well understood. In this study, the repression of CCL3 and CCL4 by IFN-γ and nitric oxide synthase 2 (NOS2) in macrophages and upon Salmonella typhimurium infection of mice was investigated. Methods. Small molecule regulators and adherent peritoneal exudates cells (A-PECs) from Nos2 �/� mice were used to identify the contribution of signaling molecules during IFN-γ–mediated in vitro regulation of CCL3, CCL4, and CXCL10. In addition, infection of bone marrow–derived macrophages (BMDMs) and mice (C57BL/6, Ifn-γ �/ , and Nos2 �/� ) with S. typhimurium were used to gain an understanding of the in vivo regulation of these chemokines. Results. IFN-γ repressed CCL3 and CCL4 in a signal transducer and activator of transcription 1 (STAT1)– NOS2–p38 mitogen activated protein kinase (p38MAPK)–activating transcription factor 3 (ATF3) dependent pathway in A-PECs. Also, during intracellular replication of S. typhimurium in BMDMs, IFN-γ and NOS2 repressed CCL3 and CCL4 production. The physiological roles of these observations were revealed during oral infection of mice with S. typhimurium, wherein endogenous IFN-γ and NOS2 enhanced serum amounts of tumor necrosis factor α and CXCL10 but repressed CCL3 and CCL4. Conclusions. This study sheds novel mechanistic insight on the regulation of CCL3 and CCL4 in mouse macrophages and during S. typhimurium oral infection.