JSM Clinical Cytology and Pathology

There is numerous evidence for the efficacy of curcumin on the treatment of infectious disease particularly tuberculosis infection. According to review of the literature, curcumin could be considered as a therapeutic option against tuberculosis; but given that immunemodulatory of curcumin in immune-response and limitation of data about the main mechanism of curcumin during tuberculosis infection; we discuss the probability of curcumin as a novel treatment option for tuberculosis disease using current evidence.

Keywords: Curcumin; Mycobacterium tuberculosis; Treatment; Tuberculosis

Tuberculosis (TB) remains as one of the most important infectious diseases in worldwide. According to WHO reports in 2018, there are 10.7 million new TB-cases, also it estimated 1.3 million deaths [1]. The lack of BCG vaccine efficacy in TB-adults and the emergence and extension of DR-TB (drug resistant-TB) strains are thecause of limit efficacy of current standard treatment of tuberculosis. In addition, anti-tuberculosis drugs particularly Isoniazid has a serious side-effect such as hepatotoxicity during the course of treatment [2,3]. Therefore, it necessary to introduce a novel generation of anti-tuberculosis therapeutic option which has efficient against both strain of susceptible and drug-resistant- TB without serious side-effects.

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadien- 3,5-dione is natural polyphenol extract of Curcuma longa plants. curcumin has several activities such as anti-oxidant, antiinflammatory, anti-cancer and antimicrobial effects [4,5]. Furthermore, curcumin not cytotoxicity on human cell lines [5]. In recent years there are several documents of anti-tuberculosis effects of curcumin during experimental studies and clinical trials [6,7]. Although the main mechanism of Curcumin against Mycobacterium tuberculosis (Mtb) remains unknown; But curcumin has immune-modulatory the effects on immune-system during tuberculosis infection [6-8]. The aim of this study was discussed about effects of curcumin on immune-system and answer this question that can curcumin be used as an anti-TB drug?.

Mycobacterium tuberculosis is commonly entered to the human body via inhalation of infected droplets from smearpositive TB individuals; innate immunity such as mucosa membrane, natural killer (NKs) and alveolar macrophage is active to fight with Mtb infection [9]. Overalls, there are four possible outcomes following infection with tubercle bacillus including: 1) aborted infection and Mtb clearance, 2) primary TB infection caused by active Mtb replication and intracellular growth, 3) latent-TB infection without clinical symptoms, and 4) Reactivation of previous TB infection via infection with multiple Mtb strains or fallen into immune-disorder complications [10]. Although the innateimmune response isimmediately activated to fight with TB infection, the innate immune system is commonly not enough [11]. Usually, innate immune cells such as dendritic cells (DCs), antigen-presenting cells (APC), alveolar macrophages and epithelial cells are inducing inflammatory process and provoke cell mediate immune-system by recognition of pathogenassociated molecular pattern molecules (PAMPs) throughout mannose receptors, complement receptors, Toll-like receptors (TLRs), Fcγ receptors, and scavenger receptors and production of pro-inflammatory cytokines [12]. Cell-mediated immunity particularly Th1 cells are responsible for appropriate response to intracellular pathogens such as Mtb infection via various pathway including 1) production of cytokines such as IL-2, IL-12, IL-1β, TNF-α and IFN-γ, 2) activation of macrophage for increasing ROS, 3) Apoptosis of infected cells by induction of CD8+ cells (CTLs), and 4) Autophagy promotion [13]. Th17 is a subgroup of Th cells which promoted recruitments of neutrophils and other PMNs to infected sites and solid granuloma formation via the production of various pro-inflammatory cytokines such as IL-6, IL-17A, IL-23 [14]. But, changing immune-response into an extension of Th2 and T regulatory cells is cause to caseous necrosis, Mtb multiply, and reactivation of previous TB infection (Table 1 and Figure 1) [15].

According the review of the literature, curcumin has inhibitory effects on maturation of dendritic cells (DCs) by decreasing the expression of CD80, CD86, and presentation of functional MHC II surface molecules [16]. In addition, Shirley et al., have shown that Curcumin can impair expression of IL-12 and other pro-inflammatory cytokines in bone marrow-derived DCs (BMDCs) of murine models; this process leads to inhibition of Th1 activation which supports intracellular growth of Tubercle bacilli within macrophages [17].

Li et al., have found that curcumin can induce apoptosis of Mtb-infected macrophages. In previous reports, it has been suggested that apoptosis of Mtb-infected macrophages is playing important role in the destruction of tubercle bacilli reservoirs cells from the body; In addition, increasing antigen presentation cells (APCs) after apoptosis of Mtb-infected macrophages can lead to activation of Th1 cells against TB [6,18]. In contrast, Shuto et al., have shown that curcumin can also inhibit the TLR2-mediated signaling pathway in macrophages which blocked Reactive oxygen species (ROS) response of Mtb-infected macrophages [19]. In addition, curcumin has inhibitory effects on NF-κB and JAK/STAT pathway which is dysregulated activation of T helpers, activation of macrophages, maturation of DCs and modulate APCs process [20].

According to present evidence, curcumin can reduce the expression and production of IFN-γ, TNF-α, IL-1, and IL-8 by its influence on NF-κB, STAT, and AP1 signaling pathways [20,21]. Castro et al., have suggested that curcumin can reduce the proliferation of Th1 cells throughout the impairment of NF-κB and T-bet signaling pathways [22]. Th1 cells activities have play determinative role against intracellular pathogens particularly, Mycobacterium tuberculosis infection by production of IFN-γ and pro-inflammatory cytokines such as IL-2 [10]. Although exacerbate activation of Th1 response can cause to host damage and tissue destruction, but cell-mediated immune-response is main responsible for the prevention of intracellular pathogens [23]. Therefore, inhibition of Th1 cells mediated activities during TB infection can associate with milliary-TB and high-actively proliferation of tubercle bacilli within macrophages [24].

Th17 cells are responsible for the recruitment and activation of neutrophils against TB infection [25]. These cells are derivate from naïve T cells by RORγt transcription factor in the effects of the production of pro-inflammatory cytokines such as IL-6 and IL-23 [26]. Th17 cells produce pro-inflammatory cytokines particularly IL-17A-F, IL-22, and IL-21which cause to the invention of innate-immune cells such as polymorphonuclear cells (PMNs) into inflammation sites and cause to create solid granuloma formation during tuberculosis infection [25,27]. Xie et al., have shown that curcumin has suppressive activities on the production of Th17 by intervention in the production of IL-17, IL-6, IL-21, RORγt, and STAT3 signaling pathway [28]. Carbone et al have found that curcumin can down-regulate expression levels of RORγt and IL-17 [29].

It has been approved that curcumin can provoke the production of T regulatory cells via activation of JAK3-STAT5 signaling pathway and over-expression of TGF-β [30]. Sakaguchi et al have shown that oral administration of curcumin could decrease immune-response in inflammatory bowel disease (IBD) cause to evaluate levels of T regulatory cells [31]. In addition, there are several experimental evidence for increasing of CD4+ and CD8+ T reg cells in murine models due to curcumin-treated allogeneic splenocytes [32,33]. T regulatory cells can suppress Th1 activities by production of IL-10 and TGF-β; there are several evidence for increasing of T regulatory cells in disseminated-TB patients [34]. Also, according to Babu et al., there are the falsenegative response of TST test in latent-TB individuals due to increasing levels of T regulatory cells [35].

Whereas, the presence of numerous documents for the efficacy of curcumin against tuberculosis infections; but the information is controversial, curcumin has immune-modulatory effects on immune-systems and influenced several types of human cell lines (Figure 2) [4-8,36]. Therefore, according to present the evidence, curcumin could not be considered as therapeutic option as ananti-tuberculosis drug due to its effects on immune-response activities particularly Th1 cells [37]. In addition, curcumin has low serum half-life and has no efficient bioavailability capacity as a pharmaceutical compound [37,38].

Information about curcumin effects on tuberculosis infection it’s limited and controversial; according to present suggestions, curcumin could not be considered as a therapeutic option against tuberculosis due to lack of selectivity, low bioavailability and modulating immune-system. Although it suggested that administration of curcumin nanoparticles can reduced hepatotoxicity effects following the isoniazid therapy.

The Ethics Committee of Mashhad University of Medical Sciences was approved the study.