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. 2019 Jan 8;234(8):12471–12482. doi: 10.1002/jcp.28103

Impact of curcumin on toll‐like receptors

Motahare Boozari 1, Alexandra E Butler 2, Amirhossein Sahebkar 3,4,5,✉
PMCID: PMC13484202  PMID: 30623441

Abstract

Toll‐like receptors (TLRs) have a pivotal role in the activation of innate immune response and inflammation. TLRs can be divided into two subgroups including extracellular TLRs that recognize microbial membrane components (TLR1, 2, 4, 5, 6, and 10), and intracellular TLRs that recognize microbial nucleic acids (TLR3, 7, 8, and 9). Curcumin is a dietary polyphenol from Curcuma longa L. that is reputed to have diverse biological and pharmacological effects. Extensive research has defined the molecular mechanisms through which curcumin mediates its therapeutic effects. One newly defined and important target of curcumin is the TLR, where it exerts an inhibitory effect. In the current study, we focus upon the TLR antagonistic effect of curcumin and curcumin's therapeutic effect as mediated via TLR inhibition. The available evidence indicates that curcumin inhibits the extracellular TLR 2 and 4 and intracellular TLR9 and thereby exerts a therapeutic effect in diseases such as cancer, inflammation, infection, autoimmune, and ischemic disease. Curcumin effectively modulates the TLR response and thereby exerts its potent therapeutic effects.

Keywords: cancer, curcumin, infection, inflammation, ischemia, TLRs

One newly defined and important target of curcumin is the toll‐like receptor (TLR), where it exerts an inhibitory effect; in the current study, we focus upon the TLR antagonistic effect of curcumin and curcumin's therapeutic effect as mediated via TLR inhibition. The available evidence indicates that curcumin inhibits the extracellular TLR 2 and 4 and intracellular TLR9 and thereby exerts a therapeutic effect in diseases such as cancer, inflammation, infection, autoimmune, and ischemic disease. Curcumin effectively modulates the TLR response and thereby exerts its potent therapeutic effects.

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1. INTRODUCTION

Toll‐like receptors (TLRs) are a major class of pattern‐recognition receptors that are activated by several types of pathogen‐associated molecular patterns (PAMPs). Upon activation, these transmembrane proteins initiate an innate immune response and inflammation in mammals, including humans (Chang, 2010). Intracellular toll–interleukin 1 (IL‐1) receptor (TIR) domains are essential for downstream signal transduction. The TIR domain mediates interactions between TLRs and adaptor proteins involved in regulating TLR signaling, including MyD88, TRIF, TRAM, and TIRAP/MAL. After ligand binding, the IκB kinase complex is activated and regulates nuclear factor‐κB (NF‐κB) related proinflammatory genes, such as tumor necrosis factor (TNF), IL‐1, and IL‐6 (Kelly et al., 2006). Ten functional TLRs have been identified in humans, including TLR1‐10. Different TLR combinations are expressed in different subsets of immune and nonimmune cell types such as monocytes, macrophages, dendritic cells, neutrophils, B and T cells, fibroblasts, endothelial cells, and epithelial cells. Cellular localization and types of PAMP ligands are factors by which TLRs can be classified:

(1) TLRs that are present on the cell surface and recognize the components of the microbial membrane such as proteins and lipids. TLR1, 2, 4, 5, 6, and 10 are included in this group.

(2) Intracellular TLRs that are present in the endoplasmic reticulum, endosomes, lysosomes, and endolysosomes. These TLRs recognize microbial nucleic acids. This group includes TLR3, 7, 8, and 9 (Kawai & Akira, 2010). Different types of TLRs, their ligands and related disease in humans are summarized in Table 1.

Table 1.

Human TLRs and their ligands and related disease

TLRs Location Cell types Ligands Related disease
TLR1 Cell surface Immune cells (T and B cells and NK cells, monocytes, macrophages), epithelial cells, and endothelial cell (Fitzner, Clauberg, Essmann, Liebmann, & Kolb‐Bachofen, 2008; Pegu et al., 2008) Makes heterodimers with TLR2 and identified lipoprotein, peptidoglycans, and lipotechoic acid (Kawai & Akira, 2010) Gram positive bacterial infection (Cook, Pisetsky, & Schwartz, 2004), inflammatory disease (Drexler & Foxwell, 2010), ischemic disease (Arslan et al., 2010)
TLR2 Cell surface Immune cells (macrophage, T, and B cells), myeloid cells, epithelial cells, endothelial cell, and dendritic cells (Fitzner et al., 2008; Lanzavecchia & Sallusto, 2001; Pegu et al., 2008) Lipopeptides, and glycans from Gram positive bacteria, HMGB1, HSP60, HSP70, and HSP96 (Chang, 2010) Gram positive bacterial infection (Cook et al., 2004)
TLR3 Intracellular Immune cells (T cells and NK cells), myeloid cells, epithelial cells, and endothelial cell (Fitzner et al., 2008; Girart, Fuertes, Domaica, Rossi, & Zwirner, 2007; Holm et al., 2009; Pegu et al., 2008) Viral double‐strand RNA (dsRNA; Zhang et al., 2007) Viral disease (O'Neill, 2003), radiation induced gastrointestinal syndrome (Takemura et al., 2014)
Self RNAs from damaged cells (Bernard et al., 2012)
TLR4 Cell surface Immune cells (T cells and NK cells, macrophages, dendritic cells), must cells, myeloid cells, epithelial cells, endothelial cell, and smooth muscle cells (Fitzner et al., 2008; Lanzavecchia & Sallusto, 2001; Pegu et al., 2008) LPS from Gram negative bacteria, lipoteichoic acid, HMGB1, HSP22, HSP60, HSP96 (Chang, 2010) Gram negative bacterial infection, immunosuppression, atherosclerosis, asthma (Cook et al., 2004), inflammatory disease (Drexler & Foxwell, 2010), ischemic disease (Arslan et al., 2010), cancer (Kelly et al., 2006)
TLR5 Cell surface Immune cells (T cells and NK cells), myeloid cells, epithelial cells, and endothelial cell (Fitzner et al., 2008; Pegu et al., 2008) Flagellin from Gram positive or Gram negative bacteria (Akira, Uematsu, & Takeuchi, 2006) Bacterial infectin (O'Neill, 2003)
TLR6 Cell surface Immune cells (T and B cells), myeloid cells, epithelial cells, and endothelial cell (Fitzner et al., 2008; Pegu et al., 2008) Makes heterodimers with TLR2 and identified lipoprotein, peptidoglycans, lipotechoic (Kawai & Akira, 2010) Gram positive bacterial infection (Cook et al., 2004)
TLR7 Intracellular Immune cells (T and B cells and NK cells), myeloid cells, endothelial cell, and dendritic cells (Fitzner et al., 2008; Girart et al., 2007; Hart, Athie‐Morales, O'Connor, & Gardiner, 2005; Lanzavecchia & Sallusto, 2001) Viral single‐strand RNA (ssRNA; Kawasaki & Kawai, 2014) Autoimmune disease (Rifkin, Leadbetter, Busconi, Viglianti, & Marshak‐Rothstein, 2005)
Viral disease (O'Neill, 2003), cancer (B. Huang, Zhao, Unkeless, Feng, & Xiong, 2008)
Streptococcus RNA in conventional dendritic cells (Mancuso et al., 2009)
TLR8 Intracellular Immune cells (NK cells), myeloid cells, epithelial cells, and endothelial cell (Fitzner et al., 2008; Hart et al., 2005) Viral and bacterial RNA (Guiducci et al., 2013) Viral disease (O'Neill, 2003)
TLR9 Intracellular Immune cells (T and B cells and NK cells), myeloid cells, epithelial cells, endothelial cell, dendritic cells (Fitzner et al., 2008; Girart et al., 2007; Lanzavecchia & Sallusto, 2001; Pegu et al., 2008) Unmethylated CpG motifs found in bacterial and viral DNA (Chang, 2010) Autoimmune disease (Rifkin et al., 2005)
Cancer (L. Huang et al., 2018)
TLR10 Cell surface Immune cells (T and B cells, monocytes, macrophages), myeloid cells, epithelial cells, and endothelial cell (Chuang & Ulevitch, 2001; Fitzner et al., 2008; Regan et al., 2013) Cooperate with TLR2 to recognize listeria ligands (Regan et al., 2013), influenza A virus infection (Lee et al., 2014) Inflammatory disease (Oosting et al., 2014)
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Note. CpG: cytidine‐phosphate‐quannosine; HMGB1: high mobility group box 1; HSP: heat shock protein; LPS: lipopolysaccharide; NK: natural killer; TLR: toll‐like receptor.

Curcumin is a polyphenol compound that imparts the yellow color of Curcuma longa L. (Zingiberaceae). Therapeutic effects of curcumin in acute and chronic inflammatory disease have been well documented (Shehzad, Rehman, & Lee, 2013). Curcumin has been reported to exert therapeutic effects against a range of diseases including cancer (Mirzaei et al., 2016), osteoarthritis (Panahi, Rahimnia, et al., 2014; Sahebkar & Henrotin, 2016), anxiety and depression (Esmaily et al., 2015; Panahi, Badeli, Karami, & Sahebkar, 2015), dyslipidemia (Cicero et al., 2017; Ganjali et al., 2017; Panahi et al., 2016), metabolic syndrome (Panahi, Hosseini, et al., 2015; Panahi, Khalili, Hosseini, Abbasinazari, & Sahebkar, 2014), respiratory diseases (Lelli, Sahebkar, Johnston, & Pedone, 2017), nonalcoholic fatty liver disease (Panahi et al., 2017; Zabihi, Pirro, Johnston, & Sahebkar, 2017), type 2 diabetes (Panahi et al., 2018; Parsamanesh, Moossavi, Bahrami, Butler, & Sahebkar, 2018), ulcerative colitis (Masoodi et al., 2018), and systemic lupus erythematosus (Momtazi‐Borojeni et al., 2017).

Many pharmacological studies have shown the therapeutic effect of curcumin in the treatment of different human diseases but curcumin is known to have low oral bioavailability. This has prompted numerous strategies to increase the absorption and bioavailability of curcumin. Today different formulations of curcumin have been prepared include liposomes, micelles, nanoparticles, and phospholipid complexes. These formulations have better bioavailability and efficacy than unformulated curcumin (Mirzaei et al., 2017; Prasad, Tyagi, & Aggarwal, 2014).

Among the pharmacological activities of curcumin, inhibition of inflammation has been well documented. The anti‐inflammatory effects of curcumin are exerted through numerous molecular targets that encompass different transcription factors, cytokines, and enzymes that are involved in the promotion or resolution of inflammation (Abdollahi, Momtazi, Johnston, & Sahebkar, 2018; Bianconi, Sahebkar, Atkin, & Pirro, 2018; Ghandadi & Sahebkar, 2017; Karimian, Pirro, Majeed, & Sahebkar, 2017; Momtazi, Derosa, Maffioli, Banach, & Sahebkar, 2016; Momtazi, Shahabipour, et al., 2016; Sahebkar, Cicero, Simental‐Mendía, Aggarwal, & Gupta, 2016). The current study focuses mainly on the TLR antagonistic effects of curcumin and its therapeutic effects mediated via TLR inhibition. We conclude that the TLR inhibitory effects of curcumin are integral to the anti‐inflammatory properties of curcumin and its therapeutic effects in a variety of diseases.

2. MOLECULAR MECHANISMS OF TLR INHIBITION BY CURCUMIN

Inflammation is a key element of the immune response to infection and may cause damage to tissue. Acute and chronic inflammation is an underlying factor in the progression of numerous diseases. Several lines of evidence have shown the anti‐inflammatory and antioxidant properties of curcumin(Sahebkar, Serban, Ursoniu, & Banach, 2015). Particularly, curcumin downregulates several proinflammatory cytokines such as TNF‐α, IL‐1, ‐2, ‐6, ‐8, mitogen‐activated protein kinase (MAPK) and suppresses the oxidative stress enzymes like nitric oxide synthase, cycloxygenase, and lipoxygenase (Goel, Kunnumakkara, & Aggarwal, 2008). Studies indicate that one of the molecular targets for the anti‐inflammatory action of curcumin is TLR modulation of inflammatory responses. TLR signaling pathway and inhibitory effects of curcumin are summarized in Figure 1.

Figure 1.

Figure 1

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The simplified TLR signaling pathway and inhibitory effects of curcumin. Curcumin is able to inhibit the extracellular TLR2/4 and inhibit TLR4 dimerization; the downstream signaling pathway of TLR 2/4 includes IRAK1, IRAK6, TRIF, and MyD88. Curcumin demonstrates an antagonist effect in the intracellular TLR9 signaling pathway. The TLR antagonistic effect of curcumin can produce an anti‐inflammatory effect. TLR: toll‐like receptor [Color figure can be viewed at wileyonlinelibrary.com]

2.1. Inhibitory effect of curcumin on the TLR4 pathway

TLR4 is a well‐known receptor that responds to bacterial lipopolysaccharide (LPS). TLR4 activation triggers a cascade of signaling events that culminate in NF‐κB overexpression and proinflammatory cytokine production and is responsible for innate immune system activation (Vaure & Liu, 2014). TLR4 dimerization is a necessary step for the activation of the downstream signaling events. LPS induces TLR4 dimerization that, in turn, leads to ligand‐independent activation of the receptor. During LPS‐induced TLR4 signaling, curcumin has been shown to exert inhibitory effects on both MyD88‐ and TRIF‐dependent pathways. Therefore, modulation of the TLR4 inflammatory response by curcumin is effected via inhibition of both ligand‐induced and ligand‐independent TLR4 dimerization (Youn, Saitoh, Miyake, & Hwang, 2006).

Myeloid differentiation protein 2 (MD‐2) is a 25‐kD glycoprotein that binds to the extracellular domain of TLR4 and, together with LPS‐binding protein and CD‐14, makes a complex that is able to recognize LPS (Fenton & Golenbock, 1998). Molecular docking studies indicate that curcumin can fit into the hydrophobic pocket of MD‐2 and that this protein is one of the important targets of curcumin in its suppression of the innate immune response (Gradišar, Keber, Pristovšek, & Jerala, 2007).

Curcumin can inhibit TNF receptor associated factor 6 (TRAF6), IL‐1 receptor–associated kinase (IRAK1), macrophage chemoattractant protein‐1 (MCP‐1), macrophage inflammatory protein‐2 (MIP‐2), and NF‐κB expression, demonstrating the modulatory impact of curcumin on the expression of TLR4 signaling pathway‐associated cytokines (Kato et al., 2004; L. Peng, Li, Song, Wang, & Xu, 2010).

2.2. The inhibitory effect of curcumin in the TLR2 pathway

TLR2 signaling and expression are necessary for innate immune system activation. Enhanced TLR2 signaling can lead to an inflammatory response. Curcumin mitigates TLR2 expression and function in monocyte and neutrophil cell lines via an oxidative process. This TLR2 downregulation effect of curcumin is effectively blocked by N‐acetyl cysteine, suggesting the role of reactive metabolites in TLR2 suppression (Shuto et al., 2010). As noted above, IRAK is essential for the TLR response. Curcumin has been reported to block IRAK thiols in a murine T‐cell line, resulting in the inhibition of IRAK recruitment to the IL‐1RI and phosphorylation of IRAK (Jurrmann, Brigelius‐Flohe, & Böl, 2005). Matsuguchi, Musikacharoen, Ogawa, and Yoshikai (2000) reported that treatment of mouse macrophages with curcumin abrogated LPS‐induced TLR2 expression and inhibited NF‐κB activation.

2.3. Inhibitory effects of curcumin on the TLR9 pathway

TLR9 is located in intracellular vesicles in immune system cells such as B‐lymphocytes, monocytes and natural killer cells, and is activated by bacterial and viral DNA (Leifer et al., 2004). TLR9 signals promote proinflammatory responses that result in the production of cytokines such as type‐I interferon, IL‐6, TNF, interferon α, and IL‐12 (Martínez‐Campos, Burguete‐García, & Madrid‐Marina, 2017). In the cancer realm, TLR9 expression varies greatly with the type of cancer and is present as a marker for several types of cancer. Upregulated TLR9 expression has been reported in breast cancer, renal cell carcinoma, ovarian cancer, prostate cancer, and non‐small‐cell lung cancer (Martínez‐Campos et al., 2017). TLR9 is also critically involved in autoimmune diseases, and there is an ongoing effort to explore the therapeutic value of synthetic TLR9 agonists and antagonists in reducing autoimmune inflammation (S. Peng et al., 2016).

C. Tu, Han, et al. (2012) reported that curcumin reduced the expression levels of TLR9 in mouse liver and acted as an anti‐inflammatory and immunomodulatory agent to treat hepatic inflammation. Furthermore, curcumin ameliorated the inflammatory signaling pathways in T lymphocytes, and TLRs play a critical role in these pathways. Curcumin decreased TLR4 and TLR9 expression in CD4+ and CD8+ T cells and thereby regulated the immune response (Chearwae & Bright, 2008).

A module‐based network analysis approach was used to identify the mechanism behind the anti‐inflammatory effects of curcumin. The analysis revealed that TLR9 is a possible target for the anti‐inflammatory effects of curcumin (Gan et al., 2015).

3. TLR‐BASED THERAPEUTIC EFFECTS OF CURCUMIN

Curcumin modulates the TLR response via different mechanisms and suppresses various diseases through its TLR inhibitory effect, as summarized in Figure 2.

Figure 2.

Figure 2

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The TLR based therapeutic effects of curcumin. Curcumin suppresses various diseases through its TLR inhibitory effect including infectious disease, inflammatory disease, autoimmune disease, ischemic disease, and cancer. Inline graphic  = in vivo study Inline graphic  = in vitro study Inline graphic  = clinical trial. TLR: toll‐like receptor [Color figure can be viewed at wileyonlinelibrary.com]

3.1. Infectious diseases

TLRs recognize different microbial‐associated molecular patterns shared by many microbes but not expressed by the host. TLR2 acts as a receptor for bacterial peptidoglycan, which is mainly present in Gram‐positive bacteria (Schwabe, Seki, & Brenner, 2006; Takeuchi & Akira, 2010). TLR2 receptor has a key role in the recognition of lipoproteins released from the cell wall of several types of bacteria (Lien et al., 1999). TLR4 is a member of the IL‐1 receptor (IL‐1R)/TLR family (Cook et al., 2004), that is, expressed on the cell surface. TLR4 recognizes LPS and triggers an inflammatory response to Gram‐negative bacteria (Meena, Verma, Verma, Ahuja, & Paul, 2013). In addition to TLR2 and TLR4, TLR9 recognizes bacterial and viral unmethylated DNA with CpG motifs (Schwabe et al., 2006; Takeuchi & Akira, 2010).

3.1.1. Urinary tract infection

Chronic urinary tract infection is one type of chronic inflammatory infectious disease. Studies have reported that many inflammatory cytokines are highly expressed in the serum of patients with chronic inflammatory infectious disease (Chaudhry et al., 2014; Morozov et al., 2016). Curcumin inhibits the messenger RNA (mRNA) expression of TLR2 and TLR4 and reduces the over‐release of inflammatory mediators, which lead to the attenuation of the inflammatory response in rats with chronic urinary tract infections (Xue, Qi, & Du, 2017).

3.1.2. Gastric infection

Helicobacter pylori activate host innate and adaptive immune responses but the persistence of the infective agent suggests that the response is insufficient to eradicate the infection. This untreated infection induces an inflammatory response. Curcumin attenuates inflammation of the gastric mucosa due to H. pylori infection with upregulation of the expression of TLRs (1, 5, 6, and 7) and inflammatory cytokines (Santos et al., 2015).

3.1.3. Respiratory tract infections

Respiratory tract infections are prevalent childhood diseases and most of the children who experience recurrent respiratory infections are not immunodeficient. Injection of TLR ligands could improve the immune response in mice infected with a respiratory influenza virus that were treated with antibiotics (Ichinohe et al., 2011). Therefore, TLR antagonists are useful therapies in respiratory infections. Curcumin and lactoferrin oral supplementation reduced infection in children with recurrent respiratory tract infections. Immunologic analyses showed that CD14+/TLR2+ expressing cells were augmented whereas CD14+/TLR4+ expressing cells were diminished. Curcumin could, therefore, be clinically beneficial in immune modulation (Zuccotti et al., 2009).

3.1.4. Malaria

Members of the TLR family have are involved in the recognition of Plasmodium falciparum. It is known that binding of microbial ligands to the respective TLRs triggers proinflammatory cytokine release mediated by the TIR domain. This proinflammatory response is a part of the host response during malaria. These findings suggest a TLR4‐mediated responses to malaria in vivo (Mockenhaupt et al., 2006). Curcumin and a combination therapy activated the TLR2‐mediated innate immune response leading to enhanced IL‐10 production and generation of antiparasitic antibodies, thereby contributing to protective immunity. These results suggest the potential value of curcumin in the prevention of recurrence in falciparum and relapse in vivax malaria (Vathsala et al., 2012).

3.1.5. Periodontal disease

Periodontal disease is a chronic inflammatory condition in which an immune response is evoked against periodontopathic bacteria present in dental biofilm. A dysfunctional host immune response against the aforementioned bacteria can lead to persistent destruction of periodontal tissue (Song et al., 2017). Recent studies have indicated that interactions between host immunity and periodontopathic bacteria may regulate the progression of periodontitis. Guimarães et al. (2012) showed that curcumin can effectively mitigate innate immune responses in periodontal disease by modulating the TLR signaling pathway.

3.1.6. Viral infection

3.1.6.1. Human immunodeficiency virus (HIV) infection

TLR stimulation is an important factor in HIV‐1 replication. Studies demonstrate that HIV‐1 infection increases TLR2 and 4 expression and production of proinflammatory cytokines that lead to response regulation to HIV‐1 infection and affect the inflammatory response (Hernández, Stevenson, Latz, & Urcuqui‐Inchima, 2012). Ferreira, Nazli, Dizzell, Mueller, and Kaushic (2015) show that pretreatment with curcumin can protect the female genital tract against HIV‐1 inflammation and prevent the chemokine upregulation due to HIV glycoprotein 120. Furthermore, curcumin blocks coinfection‐mediated direct and indirect enhancement of HIV replication in T‐cells and decreases HIV amplification in chronically infected T‐cells directly.

3.1.6.2. Herpes simplex virus (HSV) infection

HSV glycoproteins gH/gL act as a TLR2 agonist and activate the NF‐kB signaling process (Leoni, Gianni, Salvioli, & Campadelli‐Fiume, 2012). Similarly, during HSV infection, TLR2 stimulates the production of inflammatory cytokines in primary microglial cells that suggests the critical role of TLR2 in the immunopathology of HSV infection (Aravalli, Hu, Rowen, Palmquist, & Lokensgard, 2005). Curcumin pretreatment in human genital epithelial cells blocks HSV‐2 viral replication. The NFκB inhibitory effect of curcumin effectively blocked viral expulsion after reproduction in primary genital epithelial cells exposed to HSV‐2 (Ferreira et al., 2015).

3.1.6.3. Influenza infection

Excessive TLR activation is important in influenza A virus infection. TLR3 activation can lead to acute lung injury and acute pneumonia (Goffic et al., 2006). The TLR4 regulatory effect in MyD88 expression and p38 MAPK activation can modulate influenza A virus entry and tropism (Marchant et al., 2010). Furthermore, TLR7 activation is required for efficient influenza A virus replication (Pang, Pillai, & Iwasaki, 2013). An in vitro study showed that curcumin inhibits influenza A virus activation, adsorption, and replication via an antagonist effect in TLR2 and 4. Additionally, curcumin significantly improved influenza A virus‐induced acute lung injury in mice (Dai et al., 2018).

3.2. Inflammatory diseases

TLRs recognize endogenous molecules that have been shown to be present in many autoimmune diseases. The TLR signaling pathway may be one pathogenic mechanism involved in inflammatory disease, and therefore inhibition of the TLR signaling pathway is one approach to treating inflammatory disease (Drexler & Foxwell, 2010). These inflammatory diseases are discussed separately in the following sections.

3.2.1. Inflammatory bowel disease (IBD)

IBD, that includes ulcerative colitis and Crohn's disease, is a major affliction of the small and large bowel. Curcumin is effective in preventing or ameliorating ulcerative colitis and inflammation. Curcumin exerts its inhibitory effects on trinitrobenzenesulfonic acid‐induced experimental colitis via TLR4 receptor inhibition (Baliga et al., 2012; Lubbad, Oriowo, & Khan, 2009).

3.2.2. Hepatitis

Concanavalin A‐induced hepatitis is a known model of T cell‐mediated hepatitis, mimicking several features of human T cell‐mediated liver disease, including autoimmune hepatitis. Inflammatory signaling pathways and innate immune responses modulate the development of hepatitis. The expression of TLR2, TLR4, and TLR9 was upregulated in liver cells following administration of Concanavalin A. Curcumin acts as a TLR4 antagonist in vitro and inhibits LPS‐TLR4 signaling in HEK‐TLR4 cells (Gradišar et al., 2007). Furthermore, in vitro and in vivo studies demonstrated that curcumin could inhibit TLR2, TLR4, and TLR9 expression (Chearwae & Bright, 2008; Shuto et al., 2010). Therefore, curcumin might be useful in the treatment of inflammatory liver disease via inhibition of TLR2, TLR4, and TLR9 expression. Curcumin could be an effective agent in modulating the liver fibrosis induced by carbon tetrachloride via the same mechanisms. The antifibrotic activities of curcumin merit further clinical investigation for the treatment of hepatic fibrosis (C. Tu, Yao, et al., 2012).

High mobility group box 1 protein (HMGB1) is an intracellular protein that is secreted by immune cells, including macrophages, monocytes, and dendritic cells, as a cytokine mediator of inflammation (Wang et al., 1999). TLR2 and TLR4 are involved in HMGB1 signaling. HMGB1 signals via TLR4 to activate tumor antigen‐specific T cell immunity in both mice and humans (Apetoh et al., 2007). HMGB1 effectively induces IL‐8 release in human embryonic kidney (HEK293) cells transfected with TLR2 (M. Yu et al., 2006). Curcumin inhibits HMGB1 release and expression (D.‐C. Kim, Lee, & Bae, 2011; D. Tang, Kang, Zeh, & Lotze, 2011). Curcumin inhibits LPS‐mediated release of HMGB1 and HMGB1‐mediated proinflammatory responses in human endothelial cells through downregulation of the cell surface expression of the HMGB1 receptors TLR2 and TLR4 (D.‐C. Kim et al., 2011). Curcumin could be useful in the treatment of inflammatory liver disease via inhibition of HMGB1 release, expression, and cytoplasmic translocation in hepatocytes (C. Tu, Yao, Xu, & Zhang, 2013). Curcumin could be useful in hepatic fibrosis via inhibition of TLR2, TLR4, and TLR9 expression and modulation of HMGB1 (C. Tu, Yao, et al., 2012). Curcumin protects mice from Propionibacterium acnes‐induced liver injury through reduction of HMGB1 cytoplasmic translocation and TLR4 expression (Gu, Guan, Shi, Zhang, & Yang, 2015).

3.2.3. Liver fibrosis

Chronic or recurring hepatic inflammation is integral to the pathophysiology of liver fibrosis. This inflammation can be triggered through either direct or indirect damage and can be either infectious or noninfectious. Activation and proliferation of hepatic stellate cells (HSCs) can significantly contribute to the progression of hepatic fibrosis by enhancing extracellular matrix synthesis and secretion of cytokines and chemokines (Czaja, 2014). Curcumin promotes apoptosis of activated HSCs by inhibiting the expression of cytokines related to the MyD88 pathway. Hence, curcumin might promote apoptosis of HSCs via a MyD88‐dependent signaling pathway involving NF‐κB. Overall, the extant evidence presented supports a plausible preventive role of curcumin against liver fibrosis (C. Tu, Yao, et al., 2012).

3.2.4. Mastitis

Mastitis is an infectious disease in the breast and surrounding tissues. This disease is the result of the interplay between microbial and environmental factors. Escherichia coli is among the most common culprit pathogens in the pathophysiology of clinical mastitis (Burvenich, Van Merris, Mehrzad, Diez‐Fraile, & Duchateau, 2003). LPS has been identified as an important risk factor for mastitis. During intramammary E. coli infection, LPS is recognized by TLR4 leading to the induction of proinflammatory cytokines and mediators such as TNF‐α, IL‐6, and IL‐1. Curcumin exerted anti‐inflammatory effects in a LPS‐induced mouse mastitis model via inhibition of TLR4 expression and proinflammatory cytokine production. These findings suggest that curcumin may serve as a potential therapy for mastitis (Fu et al., 2014).

3.2.5. Obesity

Adipocytes express inflammatory mediators that induce chronic inflammation. Adipocytes activate the innate immune response through the TLR4/NFκB pathway and increases in proinflammatory gene expression. Reduction of adipocyte inflammation is expected to reverse this low‐grade inflammatory state, reduce cardiovascular risk and improve insulin sensitivity (Lin et al., 2000). Several studies have suggested that curcumin inhibits TLR4 activation and subsequent NF‐κB‐related proinflammatory signaling pathways. Curcumin inhibited TNFα‐activated NF‐κB signaling in adipocytes and reduced cytokine expression (Gonzales & Orlando, 2008; Weisberg, Leibel, & Tortoriello, 2008). These findings imply that curcumin may inhibit the chronic inflammatory properties of adipose tissue.

3.2.6. Parkinson's disease

Parkinson's disease is a neurodegenerative disease and neuroinflammation is closely linked with its pathophysiology. Neuroinflammation is triggered by the activation of glial cells that release inflammatory mediators such as inflammatory cytokines. Astrocytes are the most abundant type of glial cells in the brain. Astrocytes express TLRs like TLR2, TLR3, TLR4, and TLR9. S. Yu et al. (2016) demonstrated the protective effect of curcumin on 1‐methyl‐4‐phenylpyridiniumion‐(MPP+)‐stimulated primary mesencephalic astrocytes, reducing the production of proinflammatory and oxidative mediators such as TNF‐α, IL‐6, and reactive oxygen species (ROS; S. Yu et al., 2016).

3.2.7. Osteoarthritis

Studies suggest that in the upregulation of TLR4 and TLR9, other inflammatory cytokines and danger signals probably have more important roles, and stimulation with TLR4 overexpression lead to an increase in IL‐1β expression in chondrocytes. It may, therefore, be that different cytokines play different roles in upregulation of various TLRs and their positive feedback loops (Sillat et al., 2013). Curcumin exhibits an anti‐inflammatory effect in human intervertebral disc tissue (nucleus pulposus and annulus fibrosus) removed from 27 patients undergoing spinal surgery for discectomy or interbody fusion for degenerative disc disease or disc herniation by influencing TLR2 expression (Klawitter et al., 2012).

3.3. Autoimmune disease

Numerous in vitro studies have suggested that TLRs plays an important role in autoimmune disease; in particular, TLR7 and TLR9 are involved in the recognition of immune complexes. Activation of these receptors can subsequently activate immune cells, most notably B cells, and culminates in the production of several cytokines implicated in the pathogenesis of autoimmune diseases (Rifkin et al., 2005). It has been suggested that the immunomodulatory activity of curcumin may be attributed, at least in part, to the ability of this phytochemical in targeting TLRs.

3.3.1. Effects on autoimmune B cells

TLR signaling has been shown to cause a lupus‐like disease in the B‐cell activity factor (BAFF)‐overexpressing animals. In BALB/c mice stimulated with the TLR ligands LPS and CpG oligodeoxynucleotides, curcumin inhibited the proliferation of purified splenic B cells. Curcumin could also suppress LPS‐induced immunoglobulin M secretion. These findings suggest the role of curcumin as a therapeutic agent against B cell stimulation by TLR ligands. Therefore, curcumin could serve as an effective suppressor of B cell activation (Decoté‐Ricardo et al., 2009).

3.3.2. Multiple sclerosis (MS)

MS is a neurological disorder; the activation of immune cells, secretion of inflammatory cytokines, and differentiation of encephalitogenic T cells are key processes associated with its pathogenesis (Wingerchuk, Lucchinetti, & Noseworthy, 2001). Experimental allergic encephalomyelitis (EAE) is a CD4+ T cell‐mediated inflammatory demyelinating autoimmune disease of the CNS and is used as a model system to study the mechanism of MS pathogenesis (Gold, Hartung, & Toyka, 2000). Chearwae and Bright (2008) showed that 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) and curcumin ameliorate EAE by causing a significant decrease in TLR4 and TLR9 expression in CD4 + and CD8 + T cells.

3.4. Ischemic diseases

The innate immune system has an important role in initiating the inflammatory cascade in ischemia–reperfusion injury. TLRs play complex roles in ischemia–reperfusion injuries. Both TLR2 and 4 appear to be key regulators for the outcome of ischemic damage in many organs. Studies on knockout animals clearly established a central role for TLR2/4 in mediating ischemia–reperfusion injury (Arslan, Keogh, McGuirk, & Parker, 2010).

3.4.1. Cerebral ischemia

Cerebral ischemia is a severe neurodegenerative condition that induces the expression of cytokines, adhesion molecules, and other inflammatory mediators. TLRs 2/4 and the NF‐κB signaling pathway mediate the inflammatory response in cerebral ischemia. TLRs 2/4 are expressed in cerebral cortical neurons and suppress the activation of c‐Jun N‐terminal kinase that protects neurons against stroke (S.‐C. Tang et al., 2007). Curcumin inhibited TLR2/4 expression and decreased the expression and activity of NF‐κB p65 in rat brain (X. Tu et al., 2014). Furthermore, curcumin attenuated the acute inflammatory damage in traumatic brain injury by modulating the TLR4/MyD88/NF‐κB signaling pathway in microglia/macrophages (Zhu et al., 2014). Curcumin administration after spinal cord injury attenuated the TLR4/NF‐κB inflammatory signaling pathway and improved the outcome following spinal cord injury (Ni et al., 2015).

3.4.2. Cardiac ischemia

Cardiac ischemia is closely associated with cardiovascular endpoints such as myocardial infarction, heart transplantation, and coronary artery bypass surgery. TLRs are expressed in cardiomyocytes. TLR2 played a critical role in an ex vivo model of myocardial ischemia injury (Sakata et al., 2007). TLR2/4 stimulation decreased contractility of plated cardiomyocytes and significantly increased NF‐κB transcriptional activity (Boyd, Mathur, Wang, Bateman, & Walley, 2006). Curcumin, with its selective inhibition of TLR2 and HMGB1, has cardioprotective effects (Y. S. Kim et al., 2012).

3.4.3. Renal ischemia

Renal ischemia is characterized by a marked reduction in glomerular filtration rate or loss of renal parenchyma. TLRs 2/4 are expressed in both proximal and distal tubules, the thin limb of the loop of Henle and the collecting ducts (Wolfs et al., 2002). Renal ischemia plays a major role in the development of diabetic polyneuropathy (Nukada, 2014). Curcumin ameliorated diabetic polyneuropathy via reversing caveolin‐1 Tyr14 phosphorylation and subsequent suppression of TLR4 activation and inflammation (Sun et al., 2014).

3.5. Cancer

TLRs have emerged as pathological factors involved in tumorigenesis and their presence on the surface of different types of tumor cells has been demonstrated (B. Huang et al., 2008). TLRs have been reported to regulate cellular metabolism and function in melanoma, prostate, head and neck carcinoma, and breast cancer. Moreover, there is evidence suggesting the anticancer effects of TLR7 and TLR9 agonists (L. Huang, Xu, & Peng, 2018). Notably, the presence of TLR4 has been shown in many tumor types, suggesting the role of TLR4 signaling in the development and progression of cancer (Kelly et al., 2006). It has been shown that TLR4 signaling can attenuate cancer cell proliferation (Andreani, Gatti, Simonella, Rivero, & Maccioni, 2007). TLR4 also affects apoptosis by enhancing the cleavage of caspase 8 (Han et al., 2004) and ROS is thought to promote TLR 4 expression (T. Yu, Sheu, Robotham, & Yoon, 2008)

Curcumin has been widely studies as a chemopreventive and antitumor agent and its therapeutic efficacy has been shown against a variety of tumors in experimental models (Anand, Sundaram, Jhurani, Kunnumakkara, & Aggarwal, 2008). Among numerous mechanisms that have been postulated for the antitumor effects of curcumin is inhibition of TLR signaling. Curcumin is a strong inhibitor of NF‐κB, which could explain the antitumor action of this compound (Mackenzie et al., 2008). Notably, NF‐κB and MAPK pathways are activated as the result of a cascade of events triggered by TLR4‐MD2 monomer dimerization (Lu, Yeh, & Ohashi, 2008).

Malignant mesothelioma is a rare form of cancer that affects the mesothelium, and has a poor prognosis; therapeutic strategies are limited. Inflammation is integral to the pathophysiology of malignant mesothelioma. Curcumin is shown to induce pyroptosis through activation of caspase 1 and increased release of HMGB1 from mouse and human malignant mesothelioma cells. Accordingly, curcumin has a cytotoxic effect on malignant mesothelioma cells and promotes downregulation of TLR signaling pathway genes (Miller et al., 2014).

Li et al. (2014) reported that curcumin inhibited proliferation of liver cancer cells by induction of apoptosis via stimulation of intracellular ROS generation from the TLR4/Myd‐88/caspase‐8/caspase‐3 pathway. Curcumin‐induced the intracellular generation of ROS stimulated expression of TLR4, leading to cell apoptosis.

4. CONCLUSION

Curcumin is a well‐documented agent in the treatment of several diseases accompanied by acute and chronic inflammation. Curcumin is able to inhibit the inflammatory response through the downregulation of inflammatory transcription factors. This review mainly focused on the TLR antagonist effect of curcumin and therapeutic effect of curcumin through TLR inhibition. Curcumin is able to inhibit the extracellular TLR, especially TLR 2 and 4, and improve the antimicrobial effects of curcumin. Studies show the inhibitory effects of curcumin in mRNA expression of TRAF6, IRAK1, MCP‐1, MIP‐2, and NF‐κB that is essential for the TLR response and especially for TLR2 and 4 activation. Molecular docking studies show curcumin has a tendency to bind to MD‐2 protein and inhibit the latter's function in TLR 4 activation. Curcumin inhibits TLR4 dimerization and the downstream signaling pathway of TLR 4 includes TRIF and MyD88.

Furthermore, curcumin is able to inhibit the intracellular TLR9 that has an important role in cancer and autoimmune disease. Computer and experimental analysis demonstrate the antagonist effect of curcumin in TLR9 signaling pathway. These inhibitory effects of curcumin on TLR signaling pathways underpins its therapeutic effects in different diseases including cancer, inflammation, infection, autoimmune, and ischemic disease.

The current study summarizes the mechanisms of the inhibitory effect of curcumin in the TLR signaling pathway, as well as the TLR based therapeutic effects of curcumin in different diseases. We show that curcumin modulates the TLR response and the treatment of disease through regulation of this effect. Evidence from the literature indicates the potential antagonist effect of curcumin in the TLR signaling pathway, but many of the studies have been limited to animals. Therefore, it seems necessary to undertake further exploration in humans.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

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