Inflammation and inflammatory signaling pathways

Inflammation is one of the major types of immune responses. It has an important role in both innate and adaptive immunity and has a crucial role in the defense against many harmful stimuli, of both endogenous and exogenous origin (Bianchi 2007; Grivennikov et al. 2010). During the inflammatory process, several immune cells (such as leucocytes) and plasma proteins (such as cytokines, complement proteins) are brought into the site of infection or damage in tissues and subsequently activated (Dinarello 2000). These blood-derived components of the immune system mediate inflammation to eliminate invading pathogens (such as bacteria, viruses, and fungi) and also promote tissue repair (Medzhitov 2008, 2010). The immune system has evolved to recognize the molecular structures of both foreign and endogenous molecules [such as lipopolysaccharide (LPS), heat shock proteins (HSPs)] by receptors expressed by cells of the immune system such as macrophages, dendritic cells (DCs), endothelial cells, B cells, and T cells (Bianchi 2007; Mohammadi et al. 2018b; Takeuchi and Akira 2010). As a consequence of binding of these receptors to their ligands, intracellular signal transduction pathways are activated to initiate and promote inflammatory responses in immune cells against the above-mentioned agents (Gordon 2002; Mohammadi et al. 2018b; Palm and Medzhitov 2009). During the inflammatory response, several inflammatory mediators such as pro-inflammatory cytokines and chemokines are produced by immune cells (Dinarello 2000; Keyel 2014; Mohammadi et al. 2018b). The most important pro-inflammatory cytokines in the immune responses are tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-12, interferon-γ (IFN-γ), and IL-8 (Dinarello 2000; Mohammadi et al. 2018b). In addition, the interaction of the aforementioned cytokines with their receptors on the surface of immune cells also activates inflammatory signaling cascades in a positive feedback loop. The three main signaling pathways that mediate the inflammatory response in immune cells include nuclear factor-κB (NF-κB) signaling pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, and mitogen-activated protein kinase (MAPK) signaling pathway (Kyriakis and Avruch 1996; Lawrence 2009; O’shea et al. 2013). Inflammation is a protective biological response of the host immune system and is carefully controlled by several mechanisms (Hanada and Yoshimura 2002; MacDonald et al. 2011; Medzhitov 2008). However, failure in these mechanisms which tightly regulate inflammatory signaling pathways leads to unabated inflammation and generation of immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), atherosclerosis, and multiple sclerosis (MS) (Abou-Raya and Abou-Raya 2006; Barnes and Karin 1997; Brydges and Kastner 2006; Martinon and Tschopp 2004). Therefore, modulation of these signaling molecules in the inflammatory signaling pathways can effectively induce anti-inflammatory effects and could potentially be a valuable approach for the management of inflammatory diseases.

One of the natural compounds that have shown potential anti-inflammatory properties and promise in the management or control of several inflammatory diseases is curcumin. Herein, we provide a comprehensive overview of the modulatory effects of curcumin on the inflammatory signaling pathways which leads to inhibition of inflammation in different types of immune cells and animal models.

Curcumin and its immunomodulatory effects

Curcumin is a natural compound derived from Curcuma longa L. (also called turmeric, a member of Zingiberaceae family) that is being used extensively for the management of several diseases. Research supports the critical roles played by curcumin and its analogs such as antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory, hepatoprotective and anti-tumor activities (Aggarwal et al. 2009; Jalili-Nik et al. 2018; Mohammadi et al. 2018a, 2017; Momtazi and Sahebkar 2016; Momtazi et al. 2016; Panahi et al. 2016b, 2017a, b; Sahebkar 2013; Teymouri et al. 2017). In addition, it is well established that curcumin is considered to be a safe natural compound (Aggarwal et al. 2009; Jurenka 2009). In recent years, there has been an increasing interest in using curcumin as an immunomodulatory agent in the immune system. The immunomodulatory effect of curcumin arises from its interaction with a wide range of immune cells such as macrophages, DCs, B, and T cells (Abdollahi et al. 2018; Gao et al. 2004). The anti-inflammatory properties of curcumin have been demonstrated in the human and animal models of several inflammatory disorders such as RA, SLE, MS, type 1 diabetes mellitus (T1DM), atherosclerosis, metabolic syndrome, periodontal disease, colitis and Alzheimer’s disease (Abdollahi et al. 2018; Momtazi-Borojeni et al. 2017; Sahebkar et al. 2016; Soltani et al. 2019). Interestingly, recent evidence suggests that curcumin can reduce the pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1 and IL-8 via interaction with several signaling and transcription molecules such as NF-κB, JAKs/STASs, MAPKs and β-catenin (Gonzales and Orlando 2008; Han et al. 2002; Momtazi-Borojeni et al. 2017; Soetikno et al. 2011; Yang et al. 2017; Zhao et al. 2016). In this narrative review, we demonstrate that curcumin interacts with various signaling molecules in the inflammatory signaling pathways, thereby acting as an anti-inflammatory agent.

Effect of curcumin on the NF-κB signaling pathway

NF-κB was first identified in the B cells as a nuclear protein that binds specifically to kappa enhancer motif sequences in the NF-kB target genes (Sen and Baltimore 1986). This master transcription factor plays an essential role in the inducible expression of many genes associated with the inflammatory responses in the immune system including antimicrobial peptides, chemokines and cytokines (Sha et al. 1995; Xiao and Ghosh 2005). NF-κB proteins are located in the cytoplasm of the cells and repressed by their inhibitory proteins that are known as the inhibitors of NF-κB (IκBs) (Sen and Baltimore 1986). In response to various stimuli, the IκB becomes phosphorylated by an active IκB kinase (IKK), which results in the dissociation of IκB from NF-κB (Xiao and Ghosh 2005). Subsequently, NF-κB is released, translocated to the nucleus and bind their DNA binding sites to regulate the transcription of a large number of genes (Sha et al. 1995; Xiao and Ghosh 2005).

There is increasing evidence that the mode of action of curcumin involves modulating the NF-κB pathway, which may be considered as one of the key targets of curcumin (Fig. 1) (Jin et al. 2007; Kunnumakkara et al. 2007; Liu et al. 2017; Shakibaei et al. 2007; Suresh et al. 2018; Yekollu et al. 2011). The NF-κB network could be modulated at two stages: the inhibition of the NF-κB activation process, and by direct inhibition of NF-κB. In this regard, Brennan et al. reported that curcumin could inhibit NF-κB activation by inhibiting the degradation of IκB-α and reacting with the NF-kB itself in TNF-activated Jurkat T lymphoma cells (Brennan and O’Neill 1998). Curcumin may also interfere with the binding activity of NF-κB to the κB site in the IL-12p40 promoter, which significantly inhibits IL-12 production in LPS-activated macrophages (Kang et al. 1999b, c). In addition, curcumin treatment inhibited the NF-kB activation induced by oxygen–glucose deprivation in injured brain microvascular endothelial cells (BMECs) (Dong et al. 2014). Kim et al. reported that curcumin negatively regulates the production of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α) from maturing DCs (Kim et al. 2005). In addition, the curcumin-treated DCs manifested an impaired induction of TH1 responses and a normal cell-mediated immune response (Kim et al. 2005). This indicates that the inhibitory effect of curcumin on DCs maturation, at least in part, could be derived from its actions on the NF-κB activation as a potential target (Kim et al. 2005).

Fig. 1
figure 1

A schematic view of curcumin’s modulatory effects on NF-κB, JAK/STAT, and MAPKs pathway. Curcumin suppresses activation and phosphorylation of JAKs and STATs proteins. Moreover, curcumin via both direct interactions with NF-κB and IκB suppresses activation of NF-κB. Finally, curcumin inhibits MAPK signaling pathway via its interaction with three main members of this pathway including JNK, p38, and ERK. As a result of curcumin’s modulatory functions, the pro-inflammatory process including infiltration of leukocyte into the site of inflammation, activation, maturation, and also the production of pro-inflammatory mediators by innate immune cells strongly was inhibited. On the other hand, curcumin suppresses acquired immune responses by its inhibitory effects on the activation, differentiation, and cytokine production of T cells

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Further studies suggest that curcumin inhibits NF-κB signaling pathway by promoting the expression of IκB-α in activated human macrophages by influenza virus infection (Xu and Liu 2017). In addition, curcumin derivative BDMC33-treated macrophages showed an interrupted degradation of IκB, resulting in attenuation of NF-κB nuclear translocation (Lee et al. 2012). As a consequence of this event, the production of several pro-inflammatory mediators including NO, TNF-α, and IL-1β was suppressed by curcumin (Lee et al. 2012). Kumar and colleagues studied the effects of curcumin on the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) (Kumar et al. 1998). They demonstrated that the anti-inflammatory activity of curcumin may be due, in part, to the inhibition of leukocyte recruitment (Kumar et al. 1998). Curcumin blocked the TNF-induced adhesion of monocytes to HUVECs by inhibiting the expression of adhesion molecules and TNF-mediated activation of NF-κB (Kumar et al. 1998). Cho et al. reported that curcumin has an inhibitory effect on the expression of IL-1β and IL-6 expression induced in TNF-α-treated HaCaT cells (Cho et al. 2007). They suggested that curcumin exerts its anti-inflammatory and growth inhibitory effects by negative regulation of the NF-κB pathway (Cho et al. 2007). Bisdemethoxycurcumin, the active component of turmeric, suppresses the production of inflammatory cytokines including TNF-α, IL-8, and IL-6 by inhibiting the NF-κB activation and IκB degradation in pharmacologically induced inflammation in the human mast cells (Kong et al. 2018).

Pan et al. reported that a new synthetic curcumin analog (C66) decreased high glucose-induced over-expressions of intercellular adhesion molecule 1 (ICAM-1) or CD54 (an important ligand for β2 integrins), vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1). It also reduced renal macrophage infiltration and injury by suppressing NF-κB activation in diabetic mice (Pan et al. 2013).

Curcumin decreases the NF-κB activation in TCR-stimulated non-obese diabetic lymphocytes (Castro et al. 2014). Moreover, Soetikno et al. observed that the administration of curcumin protects against the development of diabetic nephropathy (Soetikno et al. 2011). Diabetic nephropathy is a major complication of diabetes and can be considered as an inflammatory disease (Gross et al. 2005). Monocytes/macrophages as the main source of pro-inflammatory mediators including TNF-α, IL-1β, and MCP-1 and are the key inflammatory cells involved in the pathogenesis of the diabetic nephropathy (Duran-Salgado and Rubio-Guerra 2014; Moreno et al. 2018). Macrophages infiltrating into the glomerulus are implicated in the development of glomerular injury (Duran-Salgado and Rubio-Guerra 2014). It has been indicated that curcumin could reduce macrophage infiltration by suppressing the activation of the NF-κB pathway in diabetic rat models (Soetikno et al. 2011). In accordance with this finding, Ghosh et al. demonstrated that curcumin treatment improves renal function in animal models with chronic renal failure by antagonizing the effect of TNF-α in peroxisome proliferator-activated receptor gamma (PPARγ) (Ghosh et al. 2009). It also blocked transactivation of NF-κB (Ghosh et al. 2009).

Effect of curcumin on JAK/STAT signaling pathway

The JAK/STAT signaling pathway is one of the most important pathways that regulate inflammation in immune cells by transducing the signal of types 1 and 2 cytokine receptors in response to various pro-inflammatory cytokines (Leonard and O’Shea 1998; O’shea et al. 2013). This pathway includes the four known Janus kinases (JAK1-3 and TYK2), which are associated with the aforementioned receptors, and seven STATs (STAT1-4, 5a, 5b, and 6) (Leonard and O’Shea 1998; O’shea et al. 2013).

In innate immunity, these intracellular molecules mediate signaling cascades induced by type I and type II interferon (i.e., IFN-α/β and IFN-γ). They can effectively induce the activation, maturation, and function of DCs and macrophages (Schindler et al. 2007). In acquired immunity, JAK/STAT signaling regulates the activation and differentiation of different subtype of T cells including TH1 (JAK2, TYK2, STAT1, and STAT4), TH2 (JAK1, JAK3, and STAT6), and TH17 (STAT3) from naïve CD4+ T cells (Leonard and O’Shea 1998; O’shea et al. 2013; Tamiya et al. 2011). Despite the physiologic roles played by JAK/STAT signaling, this pathway is also involved in the pathogenesis of several inflammatory diseases such as RA, IBD, MS, T1DM, SLE, and periodontitis, hence could be considered as a valuable target for the regulation of inflammation (Coskun et al. 2013; Haftcheshmeh et al. 2018; O’shea and Plenge 2012; O’Shea et al. 2015; STAT and EGF 2005).

The inhibitory action of curcumin on JAK/STAT signaling pathway has been confirmed in a study conducted by Kim et al. where it was shown that curcumin suppresses phosphorylation of JAK1, JAK2, and their downstream molecules such as STAT1 and STAT3 in IFN-γ, gangliosides, or LPS-activated microglial cells. As a result, the expression of several pro-inflammatory mediators including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), MCP-1 and ICAM-1 were impaired in activated microglial cells (Kim et al. 2003). In this regard, the activation of Src homology 2 domain-containing protein tyrosine phosphatases (SHP)-2, a key negative regulator of JAK activity is one of the several molecular mechanisms by which curcumin mediates the suppression of JAK activation (Kim et al. 2003). Oncostatin M (OSM) is an important member of IL-6 cytokine superfamily that is involved in the pathogenesis of several inflammatory diseases, such as RA, by inducing several matrix metalloproteinases (MMPs). In line with previous findings, it has been reported that curcumin treatment suppressed the OSM-induced phosphorylation and DNA binding activity of STAT1 (but not JAK1, JAK2, and JAK3) in bovine and human primary articular chondrocyte (Li et al. 2001). By its inhibitory action on STAT1, curcumin suppresses the OSM-induced production of MMP1, MMP3, and MMP13 in chondrocytes (Li et al. 2001). Another in vitro study assessing the mechanisms underlying curcumin-regulated JAK/STAT signaling showed that curcumin potently inhibits the expression of LPS-induced IL-6, TNF-α, and COX-2 in macrophage cell line RAW264.7 via its modulatory effect on suppressor of cytokine signaling (SOCS)1 and SOCS3 (Guimarães et al. 2013). SOCS proteins negatively regulate the overactivation of the JAK/STAT signaling in responses to inflammatory cytokines through interaction with both JAKs and STATs (Endo et al. 1997; Starr et al. 1997). This evidence provides a novel molecular mechanism by which curcumin regulates the JAK–STAT-mediated inflammatory responses in macrophages. Another in vitro study suggested that curcumin reduced the expression of several inflammatory mediators including ICAM-1, MCP-1, and IL-8 at both mRNA and protein levels by suppressing the STAT3-phosphorylation in TNF-α-stimulated HUVECs (Kim et al. 2007).

In experimental allergic encephalomyelitis (EAE), characterized by the predominance of autoreactive TH1 and TH17 cell responses, curcumin blocks the IL-12-induced phosphorylation of JAK2, TYK2, and their downstream molecules, i.e., STAT3 and SATA4 in T cells (Natarajan and Bright 2002). Curcumin also inhibits the production of IL-12 by macrophages and DCs (Kang et al. 1999a, b; Natarajan and Bright 2002). With regard to the essential role of IL-12 in the differentiation of TH1 cells (Zhu et al. 2010), curcumin can strongly suppress the proliferation and differentiation of autoreactive TH1 cells in several autoimmune diseases such as MS via inhibition of IL-12 production and its signaling cascade. Similar to effects on TH1 cells, curcumin also effectively suppresses proliferation and differentiation of autoreactive TH17 cells, another important subtype of T CD4+ cells involved in the pathogenesis of EAE (Xie et al. 2009). This is mediated by both suppressing IL-6, IL-21, and IL-17 production, and by inhibiting STAT3-phosphorylation and RAR-related orphan receptor gamma (RORγt) activation in response to the aforementioned cytokines (Xie et al. 2009). It is interesting to note that IL-6 and IL-21 are required for the differentiation of TH17 cells from naïve CD4+ T cells by activating STAT3 signaling and its downstream transcription factor of RORγt (Wei et al. 2007; Zhou et al. 2007). Curcumin treatment attenuated CNS inflammation, demyelination, and severity of clinical paralysis in animal models of EAE owing to its modulatory effects on JAK/STAT signaling (Natarajan and Bright 2002; Xie et al. 2009). This evidence is further supported by other studies which showed curcumin could exert its beneficial anti-inflammatory effects in an animal model of colitis and intestinal inflammation by inhibiting the phosphorylation of JAK2, STAT3, and STAT6 (Liu et al. 2013; Zhang et al. 2016; Zhao et al. 2016). This is followed by downregulated protein expression of TNF-α, IL-1β, IFN-γ, IL-23, and IL-12p70 and upregulated expression of anti-inflammatory cytokines including IL-4, IL-10, and IL-13 and transforming growth factor β (TGF-β) (Liu et al. 2013; Zhang et al. 2016; Zhao et al. 2016). In addition, curcumin also inhibits the activation of CD4+CD7− T cells by downregulation of the STAT-3 signaling pathway (Haftcheshmeh et al. 2019; Zhang et al. 2010a). CD4+CD7− T cells are a distinct subset of CD4+ T cells which produce TH2-like cytokine profiles including IL-4 and IL-10. They are involved in the pathogenesis of several inflammatory skin diseases (Haftcheshmeh et al. 2019).

DCs are key cells crucial for the initiation of pro-inflammatory responses in autoimmune and inflammatory diseases such as colitis and are one of the main targets of curcumin (Blanco et al. 2008; Hart et al. 2005). It has been documented that curcumin suppresses activation and maturation of DCs in colitis mice by targeting JAK/STAT signaling and also by upregulation of three important negative regulators of this pathway including SOCS 1 and 3 and protein inhibitor of activated STAT3 (PIAS3) (Zhang et al. 2016; Zhao et al. 2016).

Taken together, this growing evidence provides a better understanding of the mechanism of anti-inflammatory action for curcumin via modulating of JAK/STAT inflammatory signaling.

Effect of curcumin on MAPKs signaling pathway

MAPKs are a group of serine-threonine protein kinases that contribute to gene induction, proliferation, cellular differentiation, and inflammatory responses (Dong et al. 2002). There are three main groups of MAPKs which include extracellular receptor-activated kinase (ERK), P38, and C-Jun N-terminal kinase (JNK) (Seger and Krebs 1995). MAPKs play major roles in the production of pro-inflammatory cytokines and can be considered as valuable targets for the treatment of inflammatory diseases (Dong et al. 2002; Johnson and Lapadat 2002).

To study the effect of curcumin on inflammation related to MAPKs signaling pathway, Morgana et al. investigated its effects on LPS-stimulated raw 264.7 murine macrophages and found that curcumin remarkably reduced prostaglandin E2 (PGE2) level and the expression of TNF-α and IL-6 by inhibiting phosphorylation and activation of p38 MAPK (Guimarães et al. 2013). In addition, another in vitro study indicated that pretreatment of murine microglia cell line N9 with curcumin and demethoxycurcumin (DMC) could reduce LPS-induced phosphorylation of p38, JNK, and ERK1/2 MAPKs pathways, resulting in inhibition of the production of ROS by microglial cells (Zhang et al. 2010b). Consistent with previous studies, Kim et al. demonstrated that pretreatment of immature DCs cells with curcumin suppressed the LPS-induced maturation function of DCs by inhibiting phosphorylation of all three main MAPKs (JNK, p38, and ERK) (Kim et al. 2005). Moreover, curcumin effectively inhibited COX-2 expressions (both in mRNA and protein levels) in UVB-irradiated HaCaT cells by an inhibitory action on activation of p38 MAPK and JNK (Cho et al. 2005).

RA is a chronic inflammatory disease characterized by the infiltration of several immune cells such as macrophage, DCs, and T and B lymphocytes in the inflamed joints to produce pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, IFN-γ, IL-17, and IL-12 (Firestein and McInnes 2017). In response to these pro-inflammatory cytokines, resident synovial fibroblast cells also produce large amounts of IL-6, IL-8, COX-2, and MMPs which result in the progressive joint destruction, deformity, and disability (Huber et al. 2006; Meinecke et al. 2005). Treatment of human synovial fibroblast cell line MH7A and fibroblast-like synoviocytes (FLS) of RA patients with curcumin decreased PMA or IL-1β-induced phosphorylation of ERK1/2, but not p38, which led to reduced expression of IL-6 (Kloesch et al. 2013).

Dry eye disorder is a common inflammatory eye disease where hyperosmosis followed by the inflammation of the ocular surface is involved (Stevenson et al. 2012). In addition, high expression of pro-inflammatory cytokines such as IL-1β and IL-6 has been observed in patients with dry eye disorder (Brignole et al. 2000; Calonge et al. 2010). In a study by Min Chen et al., pretreatment of hyperosmotic-stimulated human corneal epithelial cells with curcumin prevented an increase in the IL-1β, IL-6, and TNF-α production. Interestingly, p38 inhibitor (SB 203580), but not JNK inhibitor (600125), has been able to completely inhibit the IL-1β production, suggesting that the potential anti-inflammatory effects of curcumin are mediated by its suppressive effect on the p38 pathway. Importantly, p38 inhibitor also reduced the activation of NF-κB, which proves that activation of NF-κB occurs after the activation of p38 (Chen et al. 2010). These findings provide evidence that curcumin is able to suppress NF-κB signaling cascade both through its direct interaction with NF-κB and by inhibition of its upstream activator (i.e., p38 MAPK).

After brain ischemia, brain microvascular endothelial cells (BMECs), the principal cells in the blood–brain barrier (BBB), can cause inflammation by producing several inflammatory cytokines such as IL-1β (Stanimirovic and Satoh 2000). Hence, preventing inflammatory processes in BMECs can potentially reduce brain damage. In a study by Zhan et al., curcumin was able to significantly reduce the lactate dehydrogenase (LDH) release and IL-1β production in oxygen–glucose deprivation (OGD)-stimulated BMECs via inhibition of p38 and JNK phosphorylation. In line with the Min Chen et al. study, P38 inhibitor (SB203580) suppresses activation of NF-κB, suggesting that curcumin can potentially inhibit these two pathways simultaneously (Dong et al. 2014).

In an animal model of colitis, curcumin treatment effectively reduced both myeloperoxidase (MPO) activity and production of TNF-α, COX-2 and iNOS by suppressing p38 phosphorylation. Moreover, the production of anti-inflammatory cytokine IL-10 was upregulated (Camacho-Barquero et al. 2007). These findings are in accordance with a recent study suggesting that treatment with curcumin of IBD patients with positive colonic mucosal biopsies and colonic myofibroblasts (CMF) resulted in reduced p38 phosphorylation, which was followed by a decrease in the IL-1β and MMP-3 production (Epstein et al. 2010b).

Asthma is a long-term chronic inflammatory disease characterized by the production of pro-inflammatory cytokines such as TNF-α and IL-1β in the airways (Barnes 2008; Bousquet et al. 2000). MAPKs are one of the important factors in the production of these pro-inflammatory proteins; hence, inhibiting this pathway can be a valuable treatment option for this disease (Duan and Wong 2006). In this regard, in a study by Singh et al., in an animal model of chronic asthma, intranasal curcumin was able to inhibit all of the three main pathways of MAPKs (p38, JNK, and ERK) (Chauhan et al. 2018). As a result, the levels of nitrite, COX-2, and reactive oxygen species (ROS) were significantly reduced (Chauhan et al. 2018).

Other targets of curcumin

Curcumin has also shown immunomodulatory effects on different signaling molecules in the immune cells. Yang et al. demonstrated that treatment with curcumin downregulated the expression of glycogen synthase kinase 3 (GSK-3), a negative regulator of Wnt/β-catenin signaling pathway, and upregulated the expression of β-catenin, a chief downstream transcription factor of the canonical Wnt signaling pathway, in LPS-stimulated BMDC (Yang et al. 2017). As a result, Wnt/β-catenin signaling was activated in curcumin-treated BMDC that led to the inhibition of DCs activation and maturation (Yang et al. 2017). In addition, in a mouse model of allergic asthma, administration of curcumin for 9 days attenuated asthma symptoms and inflammatory responses in the airway by activating the Wnt/β-catenin signaling pathway, especially in DCs (Yang et al. 2017).

While investigating the further molecular targets of curcumin and its anti-inflammatory effects, Cheong et al. found that treatment of mouse model of acute asthma with curcumin (200 mg/kg) decreased both mRNA and protein levels of Notch 1 receptor and its downstream transcription factor GATA binding protein 3 (GATA3), a master regulator of TH2 cell differentiation, in lung tissues (Chong et al. 2014). Notch 1–GATA3 signaling pathway plays a crucial role in the pathogenesis of allergic asthma by promoting the differentiation of TH2 cells (Fang et al. 2007; Guo et al. 2009; Hozumi et al. 2008; Park 2010). Therefore, curcumin attenuated the allergic airway inflammation by inhibiting the Notch 1–GATA3 signaling pathway and subsequent suppression of TH2 cells differentiation (Chong et al. 2014; Osborne and Minter 2007). Recently, another in vivo study has shown that curcumin can also inhibit the phosphorylation of transforming growth factor (TGF)-activated kinase 1 (TAK1) in inflamed spinal cord cells which suppresses the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in a mouse model of acute spinal injury (Zhang et al. 2017). TAK1 is one of the MAPKKK family members and a major upstream modulator for the activation of NF-κB and P38 in microglial cells (Landström 2010). Therefore, curcumin can effectively suppress activation of these important pro-inflammatory transcription factors not only through direct interaction on NF-κB, P38, but also through their upstream molecules, especially TAK1.

Anti-inflammatory effects of curcumin in clinical trials

Over the past decade, a large number of clinical studies have investigated the anti-inflammatory effects of curcumin in several diseases. In a randomized clinical trial conducted by Alizadeh et al., administration of 80 mg curcumin nanomicelle daily for 10 weeks significantly reduced the plasma levels of inflammatory mediators including TNF-α and C-reactive protein (CRP) in infertile men (Alizadeh et al. 2018). Another randomized clinical trial evaluating the anti-inflammatory effects of curcumin supplementation found that oral administration of 500 mg turmeric (containing 22.1 mg the active ingredient curcumin) for 2 months significantly reduced the serum levels of IL-8, but not TNF-α, in patients with type 2 diabetic nephropathy (Khajehdehi et al. 2011). The anti-inflammatory effects of curcumin were further supported by a randomized clinical trial conducted by Panahi et al., which found that curcumin treatment (1 g/day) effectively reduced the serum levels of TNF-α, IL-6, and MCP-1 in patients with metabolic syndrome (Panahi et al. 2016a). In addition, a decrease in the plasma levels of IL-4 and IL-6 was observed after treatment of patients with knee osteoarthritis with pure curcuminoids (1500 mg/day) for 6 weeks (Rahimnia et al. 2015). Another clinical study found that oral administration of curcuminoids (comprising curcumin, demethoxycurcumin, and bisdemethoxycurcumin) at a daily dose of 1 g for 4 weeks significantly reduced the serum concentration of IL-1β, IL-4, and vascular endothelial growth factor (VEGF), but not TNF-α, IL-6, IL-8, IFN-γ, and MCP-1 in obese individuals (Ganjali et al. 2014). Moreover, by reducing TNF-α, IL-8, IL-6, MCP-1, and hs-CRP, curcumin effectively mediated its anti-inflammatory effects in sulfur mustard-intoxicated patients with chronic pulmonary or cutaneous complications. This disease is characterized by the overproduction of several pro-inflammatory cytokines (Panahi et al. 2012, 2015). In line with the findings of previous studies, anti-inflammatory effects of curcumin were also reported in a clinical study where it has been shown that administration of curcumin (180 mg/day) for 8 weeks resulted in a reduction of serum levels of pro-inflammatory mediators including TNF-α, IL-8, IL-6, MCP-1, and hs-CRP in patients with solid tumors. As a consequence, systemic inflammation in these patients was suppressed by curcumin supplementation (Panahi et al. 2014). All of the studies reviewed here have demonstrated the anti-inflammatory effects of curcumin in several diseases by its modulatory effects on inflammatory signaling pathway as the main targets of curcumin. Table 1 summarizes the anti-inflammatory effects of curcumin in recently completed clinical trials.

Table 1 Anti-inflammatory effects of curcumin in recently completed clinical trials
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Concluding remarks

There is growing evidence that curcumin, through interaction with a diverse set of cellular and molecular targets, has an anti-inflammatory role and therefore can be considered as a valuable natural compound for managing various inflammatory diseases. Curcumin can inhibit the inflammatory process in different types of immune cells and animal models (Table 2, Fig. 1). Curcumin has been found to suppress several inflammatory cascades in immune cells which result in (1) inhibition of activation, maturation, and cytokine production of two important cells of innate immunity, i.e., macrophages and DCs, and (2) inhibition of activation, proliferation, maturation, and cytokine production of T cell subsets such as TH1, TH2, and TH17. Interestingly, curcumin as a pleiotropic molecule can simultaneously target multiple signaling molecules such as NF-κB, JAKs/STATs, MAPKs and Wnt/β catenin, suggesting its potential as a signaling molecule-targeted therapeutic agent for inflammatory and immune-related diseases.

Table 2 A brief overview of the molecular targets of curcumin and its anti-inflammatory effects; (−) and (+) signs show the negative and positive effects of curcumin on its target molecules, respectively
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