-glucans are heterogeneous polysaccharides of glucose polymer , consisting of a backbone of -(1 - 3)-linked -d - glucopyranosyl units with -(1 - 6)-linked side chains of varying distribution and length . the activity of -glucan depends on the molecular structure , size , branching frequency , structural modification , conformation , and solubility . it appears that the most active forms of -glucans contain -(1 - 3)(1 - 6 ) linkages ( 1 ) . -glucan from many mushrooms has a -(1 - 3 ) backbone with shorter -(1 - 6 ) linked branches , while -glucan from alcaligenes faecalis contains only -(1 - 3)-glucosidic linkages ( 2 ) . schizophyllan from schizophyllum commune and scleroglucan from sclerotium glucanicum both have a -(13 ) linked backbone with one -(16)-glucose substitution every three backbone residues ( 3 ) . lentinan from lentinus edodes has a -(13 ) linked backbone and two -(16 ) side chains every five residues ( 4 ) . -glucan from oat and barley are linear with -(1 - 4 ) linkage with shorter stretches of -(1 - 3 ) ( 3 ) . however , it is unclear whether -glucans having intermediate or small molecular weight have biological activities , although some of them are active in vivo . short -glucans below 5,000 - 10,000 da of molecular weight are generally inactive ( 5 ) . the optimal branching frequency is suggested as 0.2 ( 1 in 5 backbone residues ) to 0.33 . although unbranched -glucan curdlan showed proper biological activity , chemical addition of -(1 - 6 ) glucose residues to the curdlan backbone led to an increase in anti - tumor activity ( 6 ) , as highly branched -glucan has higher affinity for cognate receptors ( 7 ) . when insoluble scleroglucan is modified by sulfation or carboxymethylation , the anti - tumor activity increases ( 8) . further study is still required before we will fully understand the structure - activity relationship in -glucans . thus , the actual -glucans binding to the immune cell surface receptors in vivo may in fact be these smaller ones . however , there is no information on this topic to date . -glucans , generally called biological response modifiers , are now recognized as anti - tumor and anti - infective drugs . the most popular -glucan is lentinan , which is isolated from fruiting bodies of lentinus edodes is the most popular -glucan and is a well - known drug with anti - tumor and anti - infective activities ( 9 ) . -glucan has been shown to protect against infection by bacteria , viruses , and pathogenic microorganisms ( 10 ) . -glucan also prevents cancer promotion and progression and has synergistic anti - tumor effects with monoclonal antibodies and cancer chemotherapeutics ( 11 ) . -glucan promotes antibody - dependent cellular cytotoxicity through a biological pathway involved in carcinogenesis ( 12 ) . instead , it is believed that lentinan shows these biological activities through activation of host immune systems . traditionally , macrophages and dendritic cells are considered the main target cells of -glucans , although neutrophils , b cells , t cells , and natural killer cells are also known to be activated by -glucan . the immunomodulatory activities of -glucans are usually studied with regard to the activation of macrophages . lentinan enhances cytotoxic activity and inflammatory cytokines of primary macrophages and raw264.7 cell lines ( 13 ) . it can also enhance the phenotypic and functional maturation of dendritic cells with significant il-12 production ( 14 ) . lentinan enhances the virus - specific t cell functions induced by dna vaccine , acts as a vaccine adjuvant ( 15 ) , and increases t cell functions in tumor - bearing mice ( 16 ) and malaria - infected mice ( 10 ) . in addition , lentinan is reported to enhance t cell functions in cancer patients ( 17 ) . however , there is no report showing that lentinan directly activates t cells in vitro . it has been demonstrated that lentinan indirectly activates t cells via il-12 and ifn- produced by lentinan - activated macrophages and dendritic cells ( 18 ) . however , lentinan might be an indirect activator of t cells and t cell activation might be observed only under in vivo conditions with mixed immune cell subsets . it has been reported that lentinan increases nk cell - mediated killing of yac-1 cells both in vitro and in vivo ( 19 ) . however , this does not necessarily mean that lentinan directly activates nk cells , since total spleen cells were used in this experiment . the only clear fact is that -glucan directly activates macrophages and dendritic cells , but the effect of -glucan on other immune cells remains controversial . further in vitro studies with purified immune cell subsets are required to clarify whether -glucan directly activates these cells . macrophages and dendritic cells have typical cell surface receptors called pattern recognition receptors ( prrs ) that detect innately non - self molecules including pathogen - associated molecular patterns ( pamps ) ( 20 ) . -glucans might act as pamps and are recognized by prrs , since -glucans can not directly penetrate cell membrane due to their large molecular size ( 3 ) . the major prrs for -glucans might be dectin-1 and the roll - like receptor ( tlr ) . upon binding with -glucan , dectin-1 and tlr might inducing signaling cascade and activate immune cells . other receptors , such as complement receptor 3 ( cr3 ) , scavenge receptors ( sr ) , and lactosylceramide ( laccer ) , might be involved ( 20 ) . dectin-1 is a lectin that consists of four components : an extracellular carbohydrate - recognition domain , a short stalk region , a single transmembrane region , and a short 40 amino acid intracellular cytoplasmic tail ( 21 ) . in particular , two amino acids ( trp221 and his223 ) located near the fourth cysteine residue appear to be critical for binding of -glucans ( 22 ) . dectin-1 specifically recognizes -(1 - 3)(1 - 6 ) glucans from fungi , plants , and bacteria ( 23 ) . however , it is not reactive toward -(1 - 4 ) glucans or -mannan ( 24 ) . binding of dectin-1 with -glucans induces several signaling pathways to activate innate immune responses , such as phagocytosis , ros production , and inflammatory cytokine production ( 25 ) . the cytoplasmic tail of dectin-1 has an immunoreceptor tyrosine - based activation ( itam)-like motif ( yxxxi / lx7yxxl ) to activate tyrosine kinases ( 26 ) . upon ligand binding , tyrosines in the itam sequences are phosphorylated by src family kinases , providing a docking site for syk ( spleen tyrosine kinase ) by interacting with the two sh2 ( src homology 2 ) domains of syk ( 26 ) . the spacing between the yxxxl sequences is important to engage both sh2 domains of syk family kinase , thus contributing to enzyme activation ( 27 ) . activated phospholipase c  ( plc ) produces inositol trisphosphate and diacylglycerol ( dag ) ( 28 ) . also , syk activates the pi3k / akt pathway , mapk , nfat , and nf-b ( 29 ) tlrs are expressed on macrophages , dendritic cells , b cells , t cells and endothelial cells and are type i transmembrane receptors of a novel protein family . several ligands have been shown to bind tlrs : tlr2-zymosan , tlr3-dsrna , tlr4-lps , and tlr5-flagellin , etc . binding of specific ligands to tlrs induces several signaling pathways , such as my88-mediated signaling and trif - mediated signaling . for example , zymosan binds to tlr2/4 of macrophages and increases the cytokine production such as tnf- and il-12 via nf-b signaling ( 31 ) . -glucans isolated from plants , such as sparassis crispa , phellinus linteus , platycodon grandiflorum , cordyceps millitaris , and angelica gigas nakai , induce dendritic cell maturation through binding to tlr4 ( 32 - 37 ) . signalings downstream from tlrs or dectin-1 might cross - talk with each other ( 38 ) . zymosan can bind both dectin-1 and tlr2 , and both dectin-1/syk and tlr / myd88 signalings are required to fully induce the translocation of nf-b subunits to the nucleus ( 39 ) . cr3 acts as an opsonic receptor for the complement component and as a nonopsonic receptor for a variety of exogenous ligands . cr3 is a heterodimeric transmembrane integrin consisting of cd11b ( m ) and cd18 ( 2 ) chains . one for -glucan is located within the c terminus , while the other for ic3b ( cleaved component 3 fragment of serum complement system ) is located within the n - terminus ( 40 ) . binding of -glucan to the c - terminal lectin domain increases adhesion to microbial cells and activates ic3b pathways causing tumor cytotoxicity ( 41 ) . ligand binding of cr3 is known to mediate intracellular signaling and induce a variety of cellular responses , including adhesion , cytotoxicity , phagocytosis and migration ( 41 ) . however , whether cr3 directly binds to -glucan is still unclear . cr3-deficiency in nk cells reduced cytotoxicity , but cr3-deficient leukocytes are still capable of recognizing and responding to -glucan ( 42 ) . the -glucan of small molecular size binds to cr3 in nk cells and that of large molecular size binds dectin-1 and tlrs in macrophages and dendritic cells . laccer recognizes a variety of microbes and pathogens , including fungi , such as candida albicans , cryptococcus neoformans , and saccharomyces cerevisiae ( 43 ) . it consists of a hydrophobic ceramide and a hydrophilic sugar moiety and is identified as a receptor for -glucan ( 44 ) . the interaction of -glucan with laccer induces a number of cellular responses in vitro . in alveolar neutrophils , -glucan from pneumocystis carinii can induce the production of macrophage inflammatory protein-2 ( mip-2 ) and tnf- via nf-b and pkc signaling . blocking antibodies to laccer or cr3 are also reported to inhibit -glucan binding to and the activation of human neutrophils ( 45 ) . sr are expressed on epithelial cells , endothelial cells and myeloid cells and comprise a family of proteins that are structurally diverse and have a range of cellular functions ( 46 ) . sr were initially described in cultured macrophages in which they mediate cholesterol uptake . based on their structures , sr can be categorized into class a , b and c. sr - a has a collagen - like domain , which is essential for ligand binding ( 47 ) . sr recognizes a variety of ligands including ldl ( low - density lipoprotein ) , hdl ( high - density lipoprotein ) , selected polyanionic molecules , and a number of microbes ( 47 ) . lentinan can bind to sr and activate multiple signals , such as pi3k , akt kinase , and mapk ( 47 ) . -glucans are potent immunomodulators that have multiple activities such as anti - tumor and anti - infective activities in particular , binding of -glucan to specific receptors in macrophages and dendritic cells can induce the production of various cytokines , indirectly activating other immune cells such as t cells and b cells under in vivo conditions . systemic immunostimulation might be the main route in preventing the growth of cancer cells and infective microorganisms in the host . several -glucan receptors in macrophages and dendritic cells , such as dectin-1 and tlrs , might play a key role in the recognition of -glucans , but the exact signaling pathways downstream from the respective receptors and the cross - talk between them is unclear to date . if we can understand these issues in greater detail , -glucans might be widely used in the therapy of cancer and infectious diseases .
-glucans are naturally occurring polysaccharides that are produced by bacteria , yeast , fungi , and many plants . 
 although their pharmacological activities , such as immunomodulatory , anti - infective and anti - cancer effects , have been well studied , it is still unclear how -glucans exert their activities . 
 however , recent studies on the -glucan receptors shed some light on their mechanism of action . since -glucans have large molecular weights , they must bind surface receptors to activate immune cells . in this review , 
 we summarize the immunopharmacological activities and the potential receptors of -glucans in immune cells .