Molecular Mechanisms by Which Saturated Fatty Acids Modulate TNF-α Expression in Mouse Macrophage Lineage

Abstract

Many macrophage functions are modulated by fatty acids (FAs), including cytokine release, such as tumor necrosis factor-α (TNF-α). TNF-α is of great interest due to its role in the inflammation process observed in several diseases such as rheumatoid arthritis, atherosclerosis, and obesity. However, the mechanisms by which FA effects occur have not been completely elucidated yet. In this study, we used a mouse monocyte lineage (J774 cells) to evaluate the effect of 50 and 100 μM of saturated (palmitic and stearic acids), monounsaturated (oleic acid) and polyunsaturated (linoleic acid) FAs on TNF-α production. Alterations in gene expression, poly(A) tail length and activation of transcription factors were evaluated. Oleic and linoleic acids, usually known as neutral or pro-inflammatory FA, inhibited LPS-induced TNF-α secretion by the cells. Saturated FAs were potent inducers of TNF-α expression and secretion under basal and inflammatory conditions (in the presence of LPS). Although the effect of the saturated FA was similar, the mechanism involved in each case seem to be distinct, as palmitic acid increased EGR-1 and CREB binding activity and stearic acid increased mRNA poly(A) tail. These results may contribute to the understanding of the molecular mechanisms by which saturated FAs modulate the inflammatory response and may lead to design of associations of dietary and pharmacological strategies to counteract the pathological effects of TNF-α.

Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity

“…Specifically, heterodimetric transcription factor 1 (AP-1), consisting of transcription factor dimers from the Jun (c-Jun or JunD) transcription factor group, fos group (c-Fos), or activating transcription factors (ATFs), is fundamental to initiating a proinflammatory response (37). However, the immediate early transcription factor EGR-1 is also important for regulating the expression of inflammatory cytokines IL-6, IL-8, TNF␣, and CCL2 (11,26,64). EGR-1, a Cys2/ His2-type zinc finger transcription factor, regulates a number of cellular processes, including cellular growth, proliferation, apoptosis, and differentiation in response to an expansive range of extracellular stimuli (12,46).…”

“…EGR-1, a Cys2/ His2-type zinc finger transcription factor, regulates a number of cellular processes, including cellular growth, proliferation, apoptosis, and differentiation in response to an expansive range of extracellular stimuli (12,46). Importantly, EGR-1 has also been shown to regulate both inflammation (11,26,64) and insulin signaling (32,63) and provide a central link between metabolic disease and inflammation. EGR1 expression is regulated downstream of MAPKs through transactivation by other immediate early transcription factors (26).…”

“…that could potentially contribute to placental inflammation. Most notably, fatty acids and inflammatory cytokines have been shown to induce proinflammatory responses in variety of cellular contexts (11,47,66,69) and are elevated in obese pregnancies (50 -52, 54), suggesting lipotoxicity as a causal mechanism of placental inflammation.…”

Adipocytes Modulate the Phenotype of Human Macrophages through Secreted Lipids

“…To this end, we explored the effect of the three most abundant fatty acids detectable in ACM, as follows: oleic, palmitic, and linoleic acid on macrophage IL12p40 secretion. Although these fatty acids have been implicated in immune modulation (34)(35)(36)(37)(38), it is not known whether they can inhibit IL12 production by macrophages. As shown in Fig.…”

Efeito das gorduras interesterificadas sobre o desenvolvimento da lesão aterosclerótica em camundongos knockout para o receptor de LDL

“…De fato, em camundongos LDLr-KO submetidos a dieta hiperlipídica rica em ácidos graxos saturados e colesterol, houve aumento da concentração plasmática de MCP-1, TNF- e IL-6, concomitante com aumento do infiltrado de macrófagos na parede arterial (Wang et al, 2010). Em macrófagos da linhagem J774 estimulados com lipopolissacarídeo (LPS), os ácidos palmítico e esteárico induziram a secreção de TNF-α quando comparados aos ácidos graxos insaturados (de Lima-Salgado et al, 2011).…”