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Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA
2Correspondence: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., Baton Rouge, LA 70808, USA. E-mail: hwangdh{at}pbrc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSIGNALING COMPONENTS...DOWNSTREAM SIGNALING PATHWAYS...MODULATION OF TLR4-DERIVED...REFERENCES |
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B and expression of inducible cyclooxygenase 2 have been demonstrated. Saturated fatty acids (SFAs) acylated in lipid A moiety of LPS are essential for biological activities of LPS. It is now demonstrated that SFAs, but not unsaturated fatty acids (UFAs), induce NF-B activation and expression of COX-2 and other inflammatory markers in macrophages. UFAs inhibit COX-2 expression induced by SFAs and LPS. Additional evidence suggests that both SFA-induced COX-2 expression and its inhibition by UFAs are mediated through a common signaling pathway derived from Tlr4. These results represent a novel mechanism by which fatty acids modulate signaling pathways and target gene expression. Whether fatty acids also modulate signaling pathways and target gene expression derived from the activation of other Tlrs remains to be determined.—Hwang, D. Modulation of the expression of cyclooxygenase 2 by fatty acids mediated through Toll-like receptor 4-derived signaling pathways.
Key Words: proinflammatory markers • NF-B • lipopolysaccharide
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSIGNALING COMPONENTS...DOWNSTREAM SIGNALING PATHWAYS...MODULATION OF TLR4-DERIVED...REFERENCES |
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2
3
4
5)
and mitogen-inducible COX-2 (6
7
8
9
10
11)
. A unique feature of COX is that it is rapidly autoinactivated after the conversion of PGG2 to PGH2 leading to curtailment of product formation (12)
. Therefore, rapid de novo synthesis of COX would be required to sustain or to reinitiate PG biosynthesis. COX-2 is expressed in various types of cells in response to growth factors, oncogenes, the tumor promoter phorbol ester, cytokines, and endotoxin (6
7
8
9
10
11
, 13
14
15
16
17
18)
. It has been shown that COX-2 is overexpressed in sites of inflammation and in many types of tumor tissues (19
20
21
22)
.
Overexpression of COX-2 in tumor tissues occurs in tumor and stromal cells including macrophages (23)
. What causes the overexpression of COX-2 in such pathological states is not clearly understood. COX-2 belongs to a family of immediate early response genes that do not require precedent protein synthesis for their expression, (24)
. Therefore, elucidating the signaling pathways leading to the expression of COX-2 is a key to understanding why COX-2 is overexpressed in such pathological states and can provide critical information for identifying potential targets of modulation by pharmacological and dietary factors.
Genetic evidence that Toll-like receptor 4 (Tlr4) is a lipopolysaccharide (LPS) receptor has been reported (25
, 26)
. Results suggesting that Tlr4-derived signaling pathways are differentially modulated by types of fatty acids were also reported (27)
. This modulation represents a novel mechanism by which fatty acids regulate signaling pathways and target gene expression and a proof of the concept proposed as to how fatty acids can act as regulators of receptor-mediated signaling pathways (28)
. In light of this advancement, this review will focus on 1) signaling pathways derived from activation of Tlr4 receptor, 2) identifying molecular targets through which fatty acids modulate the signaling pathways and the expression of COX-2 as one of the target genes, and 3) pathophysiological implication of this modulation by fatty acids.
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SIGNALING COMPONENTS PARTICIPATING IN LPS-INDUCED SIGNALING PATHWAYS IN MACROPHAGES |
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TOPABSTRACTINTRODUCTIONSIGNALING COMPONENTS...DOWNSTREAM SIGNALING PATHWAYS...MODULATION OF TLR4-DERIVED...REFERENCES |
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, 30)
. However, CD14 lacks a cytoplasmic domain. Thus, there has been a puzzling question as to how CD14 transmits extracellular signals into downstream cytoplasmic signaling pathways. Recently, genetic evidence indicating that murine Tlr4 is the LPS receptor was demonstrated using two mouse strains (C3H/HeJ and C57BL/10ScCr) that are hyporesponsive to LPS (25
, 26)
. The LPS hyporesponsive C57BL/10ScCr mouse strain does not transcribe Tlr4 because they are homozygous for a null mutation. However, C3H/HeJ mice revealed a single missense mutation consisting of a C-to-A transversion at nucleotide 2135 predicting a substitution of proline for histidine at codon 712 within the cytoplasmic signaling domain [Tlr4 (P712H)]. Identification of distinct independent mutations of the same gene in LPS hyporesponsive mouse strains provided compelling genetic evidence that Tlr4 confers hyporesponsiveness in these mouse strains.
The Toll gene was originally identified in the Drosophila embryo as it plays a crucial role in defining the dorsal-ventral pattern formation (31
, 32)
. However, the Toll family proteins participate in antifungal responses in the adult fly. Cloning and sequencing of the Drosophila Toll gene have led to identification of a family of Toll-like protein homologues in mammals, plants, and insects, defined as Tlr (33
, 34
; Fig. 1
). All members contain a conserved cytosolic region termed TlR (Toll/IL-1R) domain, suggesting they may use a common immediate downstream signaling molecule.
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The significance of Toll-like receptor proteins has been underscored because these proteins are highly conserved and are now known to be involved in innate immunity in mammals, insects, and plants (33)
. The innate immune system, which is an earlier form of host defense, functions to stimulate and orient the adaptive immune response by controlling the expression of costimulating molecules. Indeed, activation of mammalian Tlrs leads to the expression of a plethora of cytokines that play direct and indirect roles in the adaptive immune system (35
, 36)
. Results from studies using Tlr2- and Tlr4-deficient mice demonstrate that Tlr4 recognizes LPS whereas Tlr2 recognizes gram-positive bacterial cell wall components (37
, 38)
. Results from in vitro studies further suggested that Tlr2 recognizes a wide variety of other microbial products including zymosan, peptidoglycan, bacterial lipoproteins, mycobacteria, and glycolipids derived from mycobacterial cell walls (35
, 36)
. Bacterial flagellin activates Tlr5 and CpG bacterial DNA signals through Tlr9 (39
, 40)
. Ligands for other Tlrs remain to be identified.
Downstream signaling components derived from the activation of Tlr4
The cytoplasmic domain of Tlr4 is highly homologous to that of interleukin 1R (IL-1R). The immediate downstream signaling component of IL-1R is known to be an adaptor protein, myeloid differentiation factor (MyD88) (41)
. MyD88 knockout mice showed an LPS hyporesponsiveness phenotype (42)
and MyD88 is coimmunoprecipitated with wild-type Tlr4, but not with the mutant Tlr4 (P712H) derived from C3H/HeJ mice (27)
. These results indicate that MyD88 is an immediate downstream signaling molecule associated with the cytoplasmic domain of Tlr4 and that hyporesponsiveness of C3H/HeJ mice to LPS is attributed to the disruption of Tlr4-mediated signaling pathways that results from the inability of the mutant Tlr4 to interact with MyD88 (27)
. MyD88, in turn, directly interacts with IL-1R-associated kinase (IRAK), which is a serine/threonine protein kinase (42)
. This interaction triggers IRAK autophosphorylation, and phosphorylated IRAK is known to directly interact with TNF receptor-associated factor 6 (TRAF6) (43)
. It was demonstrated that the dominant negative mutant form of TRAF6 inhibits IRAK or IL-1-induced activation of NF-B (44)
. Song et al. (45)
demonstrated the association of TRAF family members with NF-B-inducing kinase (NIK) through the carboxyl-terminal TRAF domain. NIK is a novel member of the mitogen-activated protein kinase kinase kinase (MEKK1) family (46)
. Overexpression of NIK leads to the activation of NF-B and the dominant negative mutant NIK inhibits NF-B activation induced by various cytokines (45
46
47)
. NIK in turn activates inhibitor B (IB) kinase (IKK
and IKKß) and activated IKKs, particularly IKKß, phosphorylate IB, resulting in the ubiquitin-mediated degradation of IB (48
, 49)
. IB forms a complex with NF-B to keep NF-B inactivated. Thus, IB degradation leads to release of the free NF-B subunits that are translocated to the nucleus and initiate gene transcription. Recently, a new molecule designated as evolutionarily conserved signaling intermediate (ECSIT) involved in IL-1R/Tlr signaling pathways has been cloned (50)
. ECSIT bridges TRAF6 to MEKK1 by directly interacting with TRAF6 and MEKK1 (50)
. The activation of MEKK1 mediated by ECSIT leads to the activation of c-JUN kinase (JNK). Together, these results indicate that activation of IL-1R or Tlr leads to the activation of both mitogen-activated protein kinase (MAPK) and NF-B signaling pathways and suggest that ECSIT is the point from which MAPK and NF-B signaling pathways diverge.
Molecules associated with the extracellular domains of Tlr4
Although postreceptor signaling pathways share the same signaling components, receptor activation procedures are different between Tlr and IL-1R. LPS interacts with LPS binding protein (LBP) to give rise to the LPS-LBP complex, which binds to CD14 (51)
. However, CD14 cannot transduce LPS signaling through the cell membrane, because CD14 does not have a cytoplasmic domain. Thus, it is assumed that CD14 functions as the coreceptor for Tlr4. Indeed, Chow et al. (52)
showed that the presence of CD14 and human Tlr4 dramatically potentiates LPS-stimulated NF-B reporter gene expression, whereas human Tlr4 alone slightly induces the reporter gene expression.
Kimoto et al. (53)
showed that the LPS response mediated through Tlr4 may require the presence of MD2, a cell surface protein that coimmunoprecipitated with Tlr4. It was also demonstrated that when MD2, a protein associated with the extracellular domain of Tlr4, was expressed, there was a marked increase in Elk-1 activity as well as phosphorylation of extracellular-signal-regulated kinases (ERKs), JNK, and p38 in response to LPS (54)
. In addition, Tlr4-mediated NF-B reporter activity and IL-8 production were enhanced by the expression of MD2 (54)
. Akashi et al. (55)
also showed that MD2 expression in Tlr4-expressing cells enhanced LPS-induced NF-B activation. Though the major downstream signaling pathways for Tlr4 are relatively well understood, it is not known how LPS, LBP, CD14, MD2, and Tlr4 interact together to transmit the signals across the cell membrane. A tentative composite signaling pathway derived from Tlr4 is depicted in Fig. 2
.
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DOWNSTREAM SIGNALING PATHWAYS LEADING TO COX-2 EXPRESSION IN LPS-STIMULATED MACROPHAGES |
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TOPABSTRACTINTRODUCTIONSIGNALING COMPONENTS...DOWNSTREAM SIGNALING PATHWAYS...MODULATION OF TLR4-DERIVED...REFERENCES |
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57
58
59)
, although the downstream signaling components derived from LPS receptors that link to activation of MAPKs are not known. Results from studies using pharmacological inhibitors for MEK1 or p38 or activators of MAPKs demonstrated that the activation of ERK1 and 2 or p38 is required but not sufficient to induce COX-2 expression (59)
. These results suggest that activation of other downstream signaling pathways, in addition to MAPKs, is required for full expression of COX-2 in LPS-stimulated macrophages.
NF-B signaling pathway
It has been well documented that LPS induces the activation of NF-B in macrophages (60)
. Human and murine COX-2 genes contain two putative NF-B sites in their 5'-flanking regions. Wadleigh et al. (61)
showed that activation of NF-B is not required for LPS-induced COX-2 expression in the murine macrophage cell line RAW 264.7. However, Rhee and Hwang (27)
demonstrated that the activation of NF-B by NIK is sufficient to induce COX-2 expression, and that LPS-induced NF-B activation and COX-2 expression are inhibited by a dominant negative mutant of NIK or IB. The constitutively active form of Tlr4 (
Tlr4) activates NF-B and COX-2 expression, and a dominant negative mutant of NIK or IB inhibits Tlr4-induced activation of NF-B and COX-2 expression in RAW 264.7 cells. LPS-induced NF-B activation and COX-2 expression are inhibited by a dominant negative mutant form of Tlr4 [Tlr4 (P712H)]. Together, these results demonstrate that Tlr4 confers LPS responsiveness as determined by NF-B activation and COX-2 expression and that NF-B activation is required for COX-2 expression in LPS-stimulated RAW 264.7 cells. Furthermore, these results suggest that signaling pathways leading to COX-2 expression in LPS-stimulated RAW 264.7 cells are similar to the downstream signaling pathways derived from the activation of Tlr4. A tentative composite signaling pathway for LPS-induced COX-2 expression is depicted in Fig. 2
. However, C3H/HeJ or C57BL/10ScCr mouse strains are hyporesponsive instead of nonresponsive to LPS. Therefore, it remains to be determined whether LPS-induced downstream signaling pathways are identical to those induced by the activation of Tlr4.
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MODULATION OF TLR4-DERIVED SIGNALING PATHWAYS AND COX-2 EXPRESSION BY FATTY ACIDS |
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TOPABSTRACTINTRODUCTIONSIGNALING COMPONENTS...DOWNSTREAM SIGNALING PATHWAYS...MODULATION OF TLR4-DERIVED...REFERENCES |
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). Removal of these O-acylated saturated fatty acids from lipid A not only results in complete loss of endotoxic activity, but also makes the lipid A act as an antagonist (62
, 63)
. It was also demonstrated that the deacylated bacterial lipoproteins were unable to activate monocyte and cytokine expression (64)
. These results suggest that the fatty acids acylated in lipid A or bacterial lipoproteins may play a critical role in ligand recognition and receptor activation.
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Saturated fatty acids, but not unsaturated fatty acids, induce COX-2 expression in RAW 264.7 cells
Saturated fatty acids induce the expression of COX, NO2, and IL-1 in RAW 264.7 cells (Fig. 4
A). Among the saturated fatty acids (C8:0-C18:0) tested, lauric acid (C12:0) was the most potent in inducing COX-2 expression (Fig. 4B
). This pattern coincides with the abundance of these fatty acids in the lipid A molecule (65)
(Fig. 5
).
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We demonstrated previously that the activation of NF-B is sufficient and required to induce maximal expression of COX-2 in LPS-stimulated RAW 264.7 cells (27)
. Lauric acid activates NF-B in a dose-dependent manner. The expression of COX-2 induced by lauric acid was inhibited by cotransfection of a dominant negative mutant of IB plasmid (66)
. Lauric acid-induced COX-2 expression was also reduced in the COX-2 promoter reporter gene containing mutated NF-B site vs. the one containing the wild-type NF-B site (66)
. These results suggest that induction of COX-2 expression by saturated fatty acids is mediated at least in part through the activation of NF-B.
Naturally occurring fatty acids are known to bind and activate PPARs (67
68
69
70
71
72)
and some of the PPAR activators induce COX-2 expression in certain cell types (73
, 74)
. The 5'-flanking region of the murine COX-2 gene contains PPAR response element (PPRE) -like sequences (66)
. Thus, it was determined whether these sequences are required for saturated fatty acid-induced COX-2 expression. The deletion of these sequences did not affect the promoter activity of the COX-2 reporter gene (66)
. In addition, a dominant negative mutant of PPAR
did not affect lauric acid-induced COX-2 expression (66)
. Together, these results suggest that saturated fatty acid-induced COX-2 expression is not directly mediated through the PPRE-like sequences in the COX-2 gene.
Saturated fatty acid-induced COX-2 expression is inhibited by a dominant negative mutant of Tlr4
The dominant negative mutant of Tlr4 derived from LPS hyporesponsive mice (C3H/HeJ) inhibits both lauric acid-induced NF-B activation and COX-2 expression (66)
. These results suggest that the upstream target in the signaling pathway through which saturated fatty acids mediate NF-B activation and COX-2 expression is Tlr4 or its associated molecules.
Unsaturated fatty acids inhibit saturated fatty acid-induced COX-2 expression
Unlike saturated fatty acids, unsaturated fatty acids not only are unable to induce COX-2 expression, but also inhibit saturated fatty acid-induced NF-B activation and COX-2 expression (Fig. 6
A–C). These results suggest that the induction of COX-2 by saturated fatty acids and its inhibition by unsaturated fatty acids are both mediated through the NF-B signaling pathway.
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Unsaturated fatty acids inhibit LPS- and Tlr4-induced COX-2 expression but not COX-2 expression induced by constitutively active MyD88 or NIK
If the inhibition of saturated fatty acid-induced COX-2 expression by unsaturated fatty acids is mediated through Tlr4 or its associated molecules, unsaturated fatty acids should also inhibit LPS-induced COX-2 expression. The results indeed show that docosahexaenoic acid (C22:6n-3) inhibits LPS-induced expression of COX-2, iNOS, and IL-1 (Fig. 7
A). Other unsaturated fatty acids tested (Fig. 6A
) also inhibit LPS-induced COX-2 expression (data not shown). Inhibition of LPS-induced NF-B activation by docosahexaenoic acid (C22:6n-3) is demonstrated by inhibition of LPS-induced degradation of IB protein (Fig. 7B
). Docosahexaenoic acid (C22:6n-3) partially inhibits Tlr4-induced COX-2 expression (Fig. 8
A). Activation of MyD88, the immediate downstream adaptor protein, leads to activation of NF-B and COX-2 expression in RAW 264.7 cells (27)
. Therefore, if the inhibition of saturated fatty acid-induced COX-2 expression by unsaturated fatty acids is mediated through Tlr4, COX-2 expression induced by the activation of signaling steps downstream of Tlr4 should not be inhibited by unsaturated fatty acids. The results in fact show that docosahexaenoic acid (C22:6n-3) is unable to inhibit COX-2 expression induced by constitutively active MyD88 or NIK (Fig. 8B, C
). These findings suggest that both induction of COX-2 expression by saturated fatty acids and its inhibition by unsaturated fatty acids are mediated through Tlr4 or molecules associated with Tlr4.
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Together, these results represent a novel mechanism by which fatty acids modulate signaling pathways and the expression of target genes. The possibility that saturated fatty acids may act as endogenous ligands for Tlr4 and perhaps other Tlrs and that unsaturated fatty acids interfere with saturated fatty acids in interacting with Tlr4 or molecules associated with Tlr4 remains to be determined. These results further suggest that cellular expression of COX-2 and other inflammatory markers in monocytes and macrophages can be differentially regulated by types of free fatty acids, which in turn can be altered by the kinds of dietary fats consumed. Similar to LPS, bacterial lipoproteins require fatty acyl groups for recognition by Tlr2 (64)
. If fatty acids also modulate Tlr2 and other Tlr-mediated signaling pathways and target gene expression in different cell types, these results would reinforce and expand the potential significance of regulation of Tlr-derived signaling pathways and target gene expression by fatty acids.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSIGNALING COMPONENTS...DOWNSTREAM SIGNALING PATHWAYS...MODULATION OF TLR4-DERIVED...REFERENCES |
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