Nutrient Modification of the Innate Immune Response

Abstract

Objective-Monocyte/macrophage inflammation is an important contributor to diabetes and cardiovascular disease.Studies have suggested saturated fatty acids (SFA) induce monocyte inflammation in a Toll-like receptor-4 -dependent manner, but recent data suggest SFA do not directly interact with Toll-like receptor-4. The present study tests the novel hypothesis that metabolism of SFA cooperatively amplifies Toll-like receptor-4 -mediated inflammation. Methods and Results-THP-1 monocytes exposed to 100 mol/L SFA in vitro for 16 hours followed by 1 ng/mL lipopolysaccharide demonstrated enhanced IL-6 and IL-8 mRNA and protein expression (Ϸ3-fold higher than the sum of individual responses to SFA and lipopolysaccharide). SFA had similar effects on THP-1 macrophages and primary human monocytes. This amplified lipopolysaccharide response could be blocked by inhibition of SFA metabolism to ceramide and restored by cell-permeable ceramide. Both SFA and ceramide activated PKC-and the mitogen-activated protein kinases Erk, JNK, and p38. Inhibition of these pathways prevented the SFA-induced increase in cytokine expression. Conclusion-These results provide evidence for potent amplification of monocyte/macrophage innate immune responses by a novel pathway requiring metabolism of SFA to ceramide and activation of PKC-/mitogen-activated protein kinases. These findings demonstrate how nutrient excess may modulate innate immune system activation and possibly contribute to development of diabetes and cardiovascular disease. Key Words: ceramide Ⅲ mitogen-activated protein kinase Ⅲ monocytes Ⅲ protein kinase C Ⅲ Toll-like receptor I n vitro and animal studies have implicated chronic inflammation in the development and progression of insulin resistance and type 2 diabetes, and in the excess cardiovascular disease risk associated with diabetes. 1 These findings closely parallel results from epidemiological studies that demonstrate plasma inflammatory markers (such as the acute phase proteins, C-reactive protein and serum amyloid A, and the proinflammatory cytokines, IL-6, IL-1␤, and possibly tumor necrosis factor-␣) as predictors, and potential mediators, of these conditions. [1][2][3] See accompanying article on page 692Monocytes and macrophages are critical cells in the development of insulin resistance and cardiovascular disease. They accumulate early in atherosclerotic lesion development and remain throughout the transition to advanced atheroma. 4 They are closely linked to the chronic inflammatory processes that underlie plaque formation. Similarly, macrophages and macrophage-derived proinflammatory factors have been detected in adipose and other tissues 5 and appear to contribute to development of insulin resistance and hyperglycemia. 6,7 Determining what factors play important roles in activating monocytes/macrophages and contribute to systemic inflammation is essential to understanding the pathophysiology of insulin resistance and cardiovascular disease.Bacterial lipopolysaccharide (LPS) is a potent inducer of inflammation in m...

Acyl-CoA Synthetase 1 Is Induced by Gram-negative Bacteria and Lipopolysaccharide and Is Required for Phospholipid Turnover in Stimulated Macrophages

“…This absence of effect on ceramide production occurred despite the fact that ACSL1-deficient macrophages exhibited decreased levels of 16:0-CoA, the precursor for de novo ceramide biosynthesis. Ceramides previously have been shown to mediate the synergistic effects of LPS and fatty acids on enhanced cytokine production in stimulated macrophages (50). The present findings therefore argue against reduced ceramide synthesis as a mechanism underlying the anti-inflammatory effects of ACSL1 deficiency.…”

Eicosapentaenoic Acid Prevents Saturated Fatty Acid-Induced Vascular Endothelial Dysfunction: Involvement of Long-Chain Acyl-CoA Synthetase

“…It is known that saturated fatty acids initiate inflammatory signaling and oxidative stress in vascular endothelial cells. While this action is said to be mediated by the Toll-like receptor-4 (TLR-4) or ceramide pathways 14,15) , their involvement is controversial. The TLR-4-mediated pathway is involved in the induction of the inflammatory response associated with the activation of the transcription factor NF-B, and p21, which is involved in cell cycle regulation, contributes to the increased expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) induced in vascular endothelial cells by ; thereby, possibly contributing to the infiltration and adhesion of monocytes in the vascular endothelium.…”

Hypothalamic dysfunction in obesity

“…Long-chain SFA have been shown to act as ligands for TLR4 (75)(76)(77)(78)(79) and mice that lack a functional form of this receptor are protected from obesity (80) and from obesity-related insulin insensitivity (81) , administration of LPS has been shown to mimic the effects of a high-fat diet on adiposity and insulin insensitivity (73) . There is a possibility that dietary SFA act synergistically to amplify the response to LPS (82) as transfected cells and cells naturally expressing TLR4 fail to respond to the fatty acids alone (83) . Whatever the ligands are that activate TLR4 its presence has been shown to be necessary for acute lipid-induced insulin insensitivity (78) .…”