**8. Immunomodulation in anti-inflammation therapy**

Nakanishi et al. found that celecoxib can alter the immune inhibitory effects of the tumour microenvironment by promoting transformation of TAMs into M1 macrophages, inhibiting tumour growth [153]. In 1968, Ikekawa et al. found that the fruiting body extracts from *Lentinus edodes*, *Trametes versicolor*, *Ganoderma tsugae*, *Flammulina velutiper* and *Tricholoma matsutake* demonstrated substantial anti-tumour activities towards transplanted tumour cells of Sarcoma 180 [154, 155]. *Autrodia comphorata*-derived beta-glucan inhibited tumour growth for Sarcoma 37, Sarcoma 180, Erlich ascites sarcoma and Yoshida sarcoma as well as inhibited LLC1 transplanted tumour growth [156]. Daily intake of *A. comphorata*-derived beta-glucan for 18 consecutive days was demonstrated to slow tumour growth and reduce the rate of metastasis [157]. Cytotoxic T-cell activity and tumour occurrence rates were observed, and the results illustrated that daily oral intake of *Grifola frondosua*-derived beta-glucan or Lentinan can enhance cytotoxic T-cell activity and reduce tumour occurrence rates [158]. The addition of a conditioned medium along with tumour cells into the progenitor cells of DCs was found to further inhibit maturation of DCs and lower the antigen-presenting capability of the DCs [159]. Tumour cells were found to secrete M-CSF, inhibiting dendritic and T-cell differentiation and anti-tumour ability [87, 159–161]. In the inflammation environment, the amounts of M1 and M2 macrophages are not equal [162]. The tumour environment contains vast quantities of transmitters such as M-CSF, IL-6, IL-10, TGF-β and COX-2 that induce tumour megakaryocytes to differentiate into M2 macrophages, which, in addition to having inferior antigen-presenting and cytotoxic abilities, also secrete factors that inhibit immune cells, resulting in enhanced immune inhibitory effects in the tumour environment [49, 98, 102–104, 109–114]. M2 macrophages in tumour bearing mice enhance tumour growth and immune inhibitory effects. They also secrete cytokines, such as IL-10 and TGF-β, in high quantities, which attract non-cytotoxic Treg cells and TH2 cells to congregate in tumour tissue; those cells inhibit the differentiation and normal function of T cells, including their cytotoxic ability, and further promote T-cell apoptosis [49, 98, 115, 163, 164]. The polarisation of TH1 and TH2 is built on cytokine patterns; polarisation begins when the antigen-presenting cells interact with naive T cells; they polarise into Type 1 (TH1) and TH2 cells in response to the type of antigen encountered [165]. TH1 and TH2 cells secrete different cytokines; TH1 cells rely on IL-2, IFN-γ and TNF, which are involved in cell-mediated immunity against pathogens, but TH2 cells depend mostly on IL-4 and IL-5, which stimulate the production of IgE antibodies and eosinophil responses, resulting in allergic diseases [166, 167]. Although an imbalanced TH1/TH2 immune response is linked to certain hypersensitivity disorders such as allergies, asthma and hay fever [168], studies have suggested that using a biological response modifier to restore the balance between TH1 and TH2 immune response can be a potential treatment option for IgE-dependent hypersensitivity [169]. *Ganoderma lucidum* is a medicinal mushroom that has been widely used as a folk medicine in Asian countries such as China and Japan for hundreds of years for its immunomodulating and anti-tumour effects. Numerous biologically available substances with immunity enhancement effects, particularly polysaccharides, have been isolated from the extract of *G. lucidum* [170].

Anti-microbial peptides are effective components of innate immunity that exist widely in biological systems. One of the specific anti-microbial peptides, hepcidin, is a 25-amino acid antibiotic peptide synthesised in the liver. Hepcidin is responsible for regulating iron balance and recycling iron in humans and mice. Studies have reported 0–100 μg/ml concentrations of hepcidin incubated with HT1080, Hep-G2 and HeLa for 24 h. The results have indicated higher growth inhibition ratios after 70 μg/ml treatment with hepcidin in HT1080 cells; the treatment has been very effective in inhibiting the growth of fibrosarcoma cells [171, 172]. Tachyplesin is an anti-microbial peptide present in the leukocytes of the horseshoe crab (*Tachypleus tridenta‐ tus*); it inhibited the growth of TSU tumour cells on the CAM of chicken embryos as well as the growth of B16 tumour cells in syngenic mice; moreover, it blocked the proliferation of both tumour and endothelial cells in culture in a dose-dependent manner, whereas proliferation was relatively unaffected in non-tumourigenic cell lines Cos-7 and NIH-3T3 [173]. D-K4R2L9 is a peptide comprised of Leu, Lys and Arg residues, totalling 15 amino acid residues that bind to and lyse B16-F10 mouse melanoma cells in culture at concentrations that do not harm normal 3T3 fibroblasts or erythrocytes; this can be conducted to prevent intravenous-injected D122 lung carcinoma cells from forming lung tumours in mice [174, 175]. Bovine lactoferricin (LfcinB), an anti-microbial peptide, is a 25-amino acid long highly basic peptide with a disulfide bridge between two cysteines, thus giving it a cyclic twisted anti-parallel β-sheet solution structure. LfcinB has been tested on neuroblastoma growth *in vivo*; nude rats carrying SH-SY-5Y xenografts were given injections of 1.0 or 2.0 mg LfcinB; these rats' cancer was significantly inhibited after LfcinB treatment, compared with untreated controls [176]. Anti-microbial peptides can activate specific innate immune responses and immunomodulatory effects in the host, even if the host is at risk or has been damaged. Furthermore, researchers have proposed that anti-microbial peptides can modulate the host's immune system through inflammatory responses and can stimulate beneficial inflammation; anti-microbial peptides might be able to inhibit tumour growth.
