br Author contributions br Conflicts of interest

Author contributions
Conflicts of interest The authors declare no competing financial interests.
Acknowledgement This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich/Transregio 166–Project C1 and grant CA 1014/1-1 to D.C.) and the IZKF Würzburg (grant B-281 to D.C.). A.G. was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg.
Introduction Vitamin D (VD), cholecalciferol, is an important factor which not only plays key roles in the calcium and phosphorus metabolisms but also participates in several body systems including modulation of immune responses [1,2]. It has been demonstrated that VD modulates both innate and adaptive immunity [3]. Accordingly, previous investigations revealed that VD receptors are expressed in the cytoplasm of immune cells [3]. Some immune cells such as dendritic cells (DCs) and macrophages can convert 25(OH) vitamin D, an intermediate metabolite of vitamin D, into active vitamin D [4]. Therefore, it has been hypothesized that VD is an important factor which modulates expression of immune cell related molecules. Accordingly, inadequate levels of VD can be associated with malfunctions of immune responses which have been reported in several immune related diseases. Several studies have shown that vitamin D have been linked to an increased risk of a number of conditions, both infectious and non-infectious, including psoriasis [5] Mycobacterium tuberculosis [6], HIV [7], cardiovascular disease [8] cancers [9], hypersensitivities [10,11], and autoimmune conditions such as type 2 [12,13] and type I diabetes[14], Behcet's disease [15] Systemic-Sclerosis [16] and Crohn's disease [17]. Additionally, recent studies revealed that the prevalence of VD deficiency is increasing world-widely and subsequently considered as a risk factor for the many disorders [18]. Thus, it seems that the roles of VD on the immune related molecules need to be evaluated. Pathogen recognition receptors (PRRs) are the important intra/surface cellular receptors which recognize pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) [19]. Toll like receptors (TLRs) are a set of immune receptors which recognize several external and internal molecules entitle PAMPs and DAMPs, respectively [20]. The molecules activate two important intracellular signaling pathways including myeloid differentiation primary response (MYD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) dependent pathways [21]. The intracellular signaling pathways activate a various ranges of pro-inflammatory transcription factors including nuclear factor kappa-light-chain-enhancer of activated Fumonisin B1 (NF-κB), activator protein 1 (AP-1) and interferon regulatory factors (IFNs) [22]. Thus, it appears that the receptors play significant roles in the functions of immune cells. Based on the important roles played by VD on the expression and functions of immune related molecules, hence, several investigations have evaluated the relation between VD and TLRs in in vitro and in vivo conditions. For instance, a study on 1,25(OH)2D3-treated monocytes showed VD can affect TLRs by blocking NF-kB/RelA translocation to the nucleus and decreasing p38 and p42/44 (ERK1/2) stress-activated protein kinase (SAPK) signaling in purified monocytes upon TLR ligand engagement [23]. Thus, it appears that there is significant relation between TLR's functions as well as expression with VD. Therefore, the aim of this review article was to present recent information about the roles of VD on the expression and functions of TLRs.
Vitamin D; structure, its receptor and physiological functions Scientists categorize VD as a steroidal hormone which regulates several functions from calcium homeostasis, bone formation to regulate immune responses via modulation of expression and functions of immune related molecules [24]. Previtamin D3 is synthesized in the human skin and then converted to inactive vitamin D through thermal-isomerization. Only after two hydroxylation steps, 1,25(OH)2D3 is formed. In the human liver cells, the microsomal isoforms of cytochrome P450 (CYP) including CYP2DII, CYPD25, CYP3A4, and CYP2R1 are the responsible enzymes to accomplish the 25-hydroxylation of VD, while, 1-hydroxylation is produced by 1-α-hydroxylase (CYP27B1) in the human kidney [25]. The kidney CYP27B1-activity is regulated in positive and negative manner by several molecules. For example, insulin-like growth factor (IGF), hypophosphatemia, hypocalcemia, calcitonin, parathyroid hormone (PTH) and growth hormone (GH) have positive effects, while, fibroblast growth factor (FGF)-23, hypercalcemia, and hyperphosphatemia have negative roles on the CYP27B1-activity ([[26], [27], [28]]. Moreover, VD functions can also be regulated by a negative feedback of 1,25(OH)2D3 itself through inducing 24-hydroxylase (CYP24) [29]. 1,25(OH)2D3 binds to the vitamin D receptors (VDRs), belonging to a super family of nuclear receptors for steroid hormones, thyroid hormones and retinoic acid [30]. VDRs are presented in different tissues, such as immune cells, bone, skin, intestine, adipose tissue, kidneys, brain, eyes, thyroid, heart, pancreatic β-cells, muscle, parathyroid and adrenal glands [31]. 1,25(OH)2D3 interacts with VDRs in the small intestine which leads to enhanced expression of the epithelial calcium channel, and various other proteins that preserve and transport calcium from the intestinal lumen into the circulation. Based on the roles of calcium and its related canals in the activation of immune cells, it has been hypothesized that VDR plays key roles in induction of an appropriate immune response. 1,25(OH)2D3 also binds with its receptor on osteoblasts and thereby stimulates the expression of the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) and hereby facilitates the maturation of osteoclast precursors to osteoclasts. As it is clear osteoclasts mobilize calcium stores from the skeleton to maintain calcium homeostasis [32]. Additionally, several immune related genes are the targets of VD-VDR complex [3]. It appears that VD regulates expression of immune related molecules using several mechanisms such as histone acetylation [33]. Overall, as it is clear, VD has spread effects on immune cells and the immune system. It inhibits B cell proliferation, differentiation and secretion of immunoglobulins [34] and also suppresses proliferation of T cells [35] and causes in a shift from a Th1 to a Th2 phenotype [36]. Additionally, it affects T cell maturation through the inflammatory Th17 phenotype and boosts the activation of T regulatory cells [37]. Total effects of these events lead to increased production of anti-inflammatory cytokines such as IL-10 and decreased production of inflammatory cytokines (IL-17, IL-21). On the other hand it has been shown that Vitamin D inhibits production of inflammatory cytokines of monocyte such as IL-1, IL-8, IL-12, IL-6 and TNF-α [38]. Furthermore vitamin D inhibits differentiation and maturation of dendritic cells (DCs), which these effects cause an immature phenotype with decreased expression of co-stimulatory molecules (CD40, CD80 and CD86), IL-12 and MHC class II molecules [39]. Consequence of these alterations in DCs, production of the tolerogenic interleukin IL-10 increased and therefore leads to reduced antigen presentation [40]. Based on the aforementioned data regarding the roles of VD on the immune cells, it has been hypothesized that VD may modulate immune responses via alteration in TLRs expression and functions.