Macrophages derived from C3H/HeJ ( Lpsd ) mice respond to bacterial lipopolysaccharide by activating NF- χ B

159

103

Mammalian cells recognize LPS from Gram-negative bacteria via the Toll-like receptor 4 (TLR4) complex. During experimental Salmonella infection, C3H/HeJ mice carrying a dominant-negative mutation in TLR4 exhibited delayed chemokine production, impaired NO generation, and attenuated cellular immune responses. However, dramatically enhanced bacterial growth within the Kupffer cell network before the recruitment of inflammatory cells appeared to be primarily responsible for the early demise of Salmonella-infected TLR4-deficient mice. LPS-TLR4 signaling plays an essential role in the generation of both innate and adaptive immune responses throughout the course of infection with Gram-negative bacteria. Alternative pattern-recognition receptors cannot completely compensate for the loss of TLR4, and compensation occurs at the expense of an increased microbial burden.

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Dependence of Innate and Adaptive Immunity to Salmonella: Importance of the Kupffer Cell Network

Vázquez‐Torres

Vallance

Bergman

et al. 2004

159

103

“…Macrophages from LPS nonresponder mice (C3H/HeJ) still respond to LPS with NF-B activation (33), implying that, although TLR4 is required for LPS-inducible gene expression, it is not essential for NF-B mobilization in response to LPS. Indeed, TNF-␣ induction by LPS in RAW264 cells is primarily a post-transcriptional event (34), and the mechanism of IL-6 regulation in BMMs or RAW264 cells is yet unknown.…”

Section: Discussionmentioning

confidence: 99%

A Novel Pathway Regulating Lipopolysaccharide-Induced Shock by ST2/T1 Via Inhibition of Toll-Like Receptor 4 Expression

Sweet

Leung

Kang

et al. 2001

236

205

ST2/ST2L, a member of the IL-1R gene family, is expressed by fibroblasts, mast cells, and Th2, but not Th1, cells. It exists in both membrane-bound (ST2L) and soluble forms (ST2). Although ST2L has immunoregulatory properties, its ligand, cellular targets, and mode of action remain unclear. Using a soluble ST2-human IgG fusion protein, we demonstrated that ST2 bound to primary bone marrow-derived macrophages (BMM) and that this binding was enhanced by treatment with LPS. The sST2 treatment of BMMs inhibited production of the LPS-induced proinflammatory cytokines IL-6, IL-12, and TNF-α but did not alter IL-10 or NO production. Treatment of BMMs with sST2 down-regulated expression of Toll-like receptors-4 and -1 but induced nuclear translocation of NF-κB. Administration of sST2 in vivo after LPS challenge significantly reduced LPS-mediated mortality and serum levels of IL-6, IL-12, and TNF-α. Conversely, blockade of endogenous ST2 through administration of anti-ST2 Ab exacerbated the toxic effects of LPS. Thus, ST2 has anti-inflammatory properties that act directly on macrophages. We demonstrate here a novel regulatory pathway for LPS-induced shock via the ST2-Toll-like receptor 4 route. This may be of considerable therapeutic potential for reducing the severity and pathology of inflammatory diseases.

“…Such mechanisms of LPS-induced signaling may play a role in the up-regulation of the EP 2 gene. Indeed, the activation of NF-B upon LPS treatment in C3H/ HeJ macrophages has been reported (41), and this event may be involved in the up-regulation of the EP 2 gene.…”

Section: Mechanisms Underlying the Down-regulation Of Ep 4 Gene Exprementioning

confidence: 98%

The Expression of Prostaglandin E Receptors EP2 and EP4 and Their Different Regulation by Lipopolysaccharide in C3H/HeN Peritoneal Macrophages

Ikegami

Sugimoto

Segi

et al. 2001

110

102

The expression and regulation of the PGE receptors, EP2 and EP4, both of which are coupled to the stimulation of adenylate cyclase, were examined in peritoneal resident macrophages from C3H/HeN mice. mRNA expression of EP4 but not EP2 was found in nonstimulated cells, but the latter was induced by medium change alone, and this induction was augmented by LPS. mRNA expression of EP4 was down-regulated by LPS but not by medium change. PGE2 increased the cAMP content of both LPS-treated and nontreated cells. ONO-604, an EP4 agonist, also increased cAMP content in nonstimulated cells and in cells treated with LPS for 3 h, but not for 6 h. Butaprost, an EP2 agonist, was effective only in the cells treated with LPS for 6 h. The inhibitory effects of ONO-604 on TNF-α and IL-12 production were equipotent with PGE2 at any time point, but the inhibitory effects of butaprost were only seen from 14 h after stimulation. PGE2 or dibutyryl cAMP alone, but not butaprost, reduced EP4 expression, and indomethacin reversed the LPS-induced down-regulation of EP4, indicating that the down-regulation of EP4 is mediated by LPS-induced PG synthesis and EP4 activation. Indeed, when we used C3H/HeJ (LPS-hyporesponsive) macrophages, such reduction in EP4 expression was found in the cells treated with PGE2 alone, but not in LPS-treated cells. In contrast, up-regulation of EP2 expression was again observed in LPS-treated C3H/HeJ macrophages. These results suggest that EP4 is involved mainly in the inhibition of cytokine release, and that the gene expression of EP2 and EP4 is differentially regulated during macrophage activation.