Lipopolysaccharide-driven Th2 Cytokine Production in Macrophages Is Regulated by Both MyD88 and TRAM

Abstract

Gram-negative bacterial lipopolysaccharide (LPS) activates macrophages by interacting with Toll-like receptor 4 (TLR4)and triggers the production of various pro-inflammatory Th1 type (type 1) cytokines such as IFN␥, TNF␣, and IL8. Though some recent studies cited macrophages as potential sources for Th2 type (type 2) cytokines, little however is known about the intracellular events that lead to LPS-induced type 2 cytokines in macrophages. To understand the mechanisms by which LPS induces type 2 cytokine gene expression, macrophages were stimulated with LPS, and the expression of IL-4 and IL-5 genes were examined. LPS, acting through TLR4, activates both type 1 and type 2 cytokine production both in vitro and in vivo by using macrophages from C3H/HeJ or C3H/HeOuJ mice. Although the baseline level of both TNF␣ and IL-4 protein was very low, TNF␣ was released rapidly after stimulation (within 4 h); however, IL-4 was released after 48 h LPS stimulation in secreted form. Silencing of myeloid differentiation protein (MyD88) and TRIF-related adaptor molecule (TRAM), using small interfering RNA abolished IL-4 induction induced by LPS whereas silencing of TRAM has no effect on TNF␣ induction, thereby indicating that LPS-induced TNF␣ is MyD88-dependent but IL-4 is required both MyD88 and TRAM. These findings suggest a novel function of LPS and the signaling pathways in the induction of IL-4 gene expression.

Influence of LPS, TNF, TGF-�1 and IL-4 on the expression of MMPs, TIMPs and selected cytokines in rat synovial membranes incubated in vitro

“…1 and 2). Previous studies have shown that macrophages express TNF mRNA (43) and that LPS augments their TNF expression at both the mRNA and protein levels (44,45). Secretion of TNF by adipose tissue has also been described (37,46,47), but it presumably had originated from macrophages residing within the tissue (48).…”

Cholate-Containing High-Fat Diet Induces the Formation of Multinucleated Giant Cells in Atherosclerotic Plaques of Apolipoprotein E−/− Mice

“…[15][16][17] An increased serum level of IL-4 might be the result of a high endotoxin concentration because LPS drives the production of both Th1 and Th2 cytokines. 27 Zhou et al 18 have shown that feeding apoEϪ/Ϫ mice an HFD containing 1.25% cholesterol and 0.5% cholic acid induces a shift from the Th1-type to the Th2-type immune response, with increased IL-4 expression.…”

Down-regulation of ATP-binding cassette transporter G1 expression by unmethylated CpG oligodeoxynucleotides in RAW 264.7 macrophages

“…Pathogenesis by LPS is due to strong Th2 immune deviation (Mukherjee et al, 2009). However, CpG ODNs are able to inhibit the established Th2 immune responses against antigen, converting these to Th1 immune responses.…”