br Introducing toll like receptors TLRs are the

Introducing toll like receptors TLRs are the most important receptors which are expressed on the cytoplasmic and internal vesicles membrane. They have a similar structure including a leucine-rich repeats (LRRs) domain which is out of 5104 membrane, a hydrophobic transmembrane and a toll/interleukin-1 receptor (TIR) domain which is in the cytoplasm and interacts with the intracellular signaling molecules such as MYD88 and TRIF [41]. More than 11 TLRs are described and 10 have been reported in human. TLR1, 2, 4, 5 and 6 are expressed on the cytoplasmic membrane and TLR3, 7, 8 and 9 are expressed on the vesicles membrane [42]. TLR2 recognizes its ligand in combination with TLR1 and 6 [20], while, other TLRs recognize their ligands alone [22,43]. TLRs recognize wide ranges of ligands including PAMPs and DAMPs [42]. The most important ligands which are recognized by TLR1/2, 2/6, 2, 3, 4, 5, 6, 7, 8, 9 and 10 are bacterial diacylated lipopeptides/lipoteichoic acid, bacterial lipopeptides, ds-RNA, lypopolysacharide (LPS), bacterial flagellin, ssRNA, ssRNA and dsDNA, respectively [[42], [43], [44]]. Table 1 lists TLRs and their famous ligands.
TLRs and vitamin D
Conclusion Based on the aforementioned investigations, VD has dual roles in the regulation expression and functions of TLRs. Additionally, there are some documents which identify TLRs participate in either production or catabolism of activated forms of VD in cytokine dependent manner [4]. Thus, we are unable to describe a definite role for VD on the functions of TLRs and vice versa. It may be hypothesized that several factors may affect the VD functions. For example, it appears that population-based differences can be considered an important factor for response to VD to regulate TLRs functions, because there is a document that revealed that VD enhances macrophage responses to Mycobacterium tuberculosis following TLR2/1/ligand interaction in a Canadian Caucasian but not in a Canadian First Nation (Indigenous) study group [99]. Additionally, epigenetic factors also can affect the effects of VD on the function and also expression of TLRs. As mentioned in the previous section, TLR1/2 ligands leads to increased expression of VDR and CYP27B1, accordingly, a study showed that miro-RNA-21 target TLR1/2 heterodimer and its signaling pathway to down-regulate CYP27B1 in leprosy [100]. Additionally, it appears that the positive and negative relations of TLRs with VD concentrations are dependent on VD status in human, because Kim et al., reported that VD administration has positive and negative relations with TLR2 and 4 expression in VD normal and deficient individuals [101]. Collectively, it appears that VD participates in regulation of expression of several immune related factors including increased responses to pathogens and modulation of immune responses during hypersensitivities. VD also participates in modulation of other TLRs-dependent immune responses rather than infectious diseases and hypersensitivities. For example, Liao et al., revealed that maternal serum levels of VD is significantly associated with production of IL-10 in response to TLR3 and 7 ligands [102]. IL-10 plays key roles in the physiology of pregnancy and term delivery [103]. So, it appears that VD also participates in induction of a normal pregnancy in TLRs dependent manner.
Effects of estradiol outside the nucleus are often mediated by classical estrogen receptors Today, it is widely accepted that steroid hormones can signal in ways that do not rely on receptors acting in the nucleus, including activation of receptors localized to the cellular membrane. Rapid effects of estradiol were first observed in uterine tissue over 50 years ago (Szego and Davis, 1967). Increased concentrations of cAMP induced by estradiol administration occurred within seconds, outside the timeframe that was traditionally attributed to actions of steroid hormones. These rapid effects indicated that alternate signaling mechanisms must exist, and it was hypothesized even at that time that these actions of estradiol were mediated by membrane-localized receptors. Subsequent support for this theory came from radioactive ligand binding assays that showed that synaptic plasma membranes have binding sites for estradiol (Towle and Sze, 1983), and from observations of estrogen receptors on the plasma membrane in Xenopus oocytes (Sadler et al., 1985; Sadler and Maller, 1982). The idea that estrogen receptors were physiologically active at the surface membrane was highly contentious, with these early findings often dismissed as technical artifacts. Nevertheless, the field persisted, accumulating more and more evidence of membrane-localized estrogen receptors (Chaban et al., 2003; Kelly et al., 1999; Kelly and Levin, 2001; Levin, 2001; Razandi et al., 1999, Razandi et al., 2003).