, 2005, 2008; Tieu et al., 2010). It has also been shown that subjects with allergic and non-allergic rhinitis have a tendency to display reduced levels of HBDs in the nasal mucosa (Vanhinsbergh et al., 2007). Furthermore, many studies have investigated the levels of HBDs in atopic dermatitis and reported both enhanced as well as reduced levels (Asano et al., 2008; Kisich et al., 2008; Harder et al., 2010). To explore the mechanism behind this website the diminished levels of HBD1-3 in patients with AR, tonsillar tissue was cultured in the absence or presence of IL-4, IL-5, IL-13 or histamine. Neither the HBD mRNA levels nor the amount of HBDs

released into the media were affected by the culture procedure. Since our impression was that the lack of effects might be related to the use of a heterogeneous group of tonsils in terms of cells present in the excised piece, microbial growth and atopic status, we repeated the experiments with isolated tonsillar lymphocytes and AECs. The epithelial production of HBDs was found to be markedly repressed by IL-4, IL-5, IL-13 and histamine, whereas AZD2281 concentration no such effect was seen in the lymphocyte experiments. This suggests that the HBD release is regulated by epithelial cells in response to a Th2-dominated

micro-environment. An over-expression of Th2 cytokines in the skin of patients with atopic dermatitis has been reported to cause a reduction of HBD2 and HBD3, something that has been related

to the increased amount of skin infections seen among these patients (Howell et al., 2006; Howell, 2007). Moreover, the Th2 cytokines IL-4 and IL-13 have been found to inhibit the expression of AMPs by keratinocytes in response to inflammatory stimuli (Kisich et al., 2008). Another study explored the relation between Th2 cytokines and the innate immune function of human sinonasal epithelial cells in patients with chronic rhinosinusitis with nasal polyps, showing decreased expression of HBD2 in response to IL-4 and IL-13 (Ramanathan et al., 2008). In contrast, recent results suggest that prolonged exposure (2 weeks) to Clomifene Th2 cytokines in airway epithelia increases the expression and release of AMPs, including HBD2 (Zuyderduyn et al., 2011). Disruption of the epithelial lining and consequent alteration in the epithelial barrier resistance and ion transport are associated with AR and nasal mucosal inflammation (Parameswaran et al., 2006). In addition to this, reduced levels of e.g. psoriasin, calmodulin and Toll-like receptors have been linked to allergic disease (Bryborn et al., 2005, 2008; Vanhinsbergh et al., 2007). Our finding of a reduced HBD production in AR complements previous data, but also shows that this is of importance in tonsils and not only locally in the nasal compartment.

Cells were stimulated with anti-CD3 antibody (1:1000 dilution; ATCC) for 72 h. All cultures were pulsed with 20 μCi tritiated [3H]-thymidine (GE Healthcare, Little Chalfont, UK) for the last 18 h and the uptake measured on a Topcount scintillation

counter (Perkin Elmer, Cambridge, UK). Proliferation was determined as counts per minute (cpm) ± standard IWR-1 mw error of the mean (s.e.m.). Supernatants were harvested and stored in aliquots at −80°C until required. IL-2, IL-17, IL-10, TNF-α and interferon (IFN)-γ concentrations were determined using the human FlowCytomix Simplex kits (Bender MedSystems GmbH, Vienns, Austria), according to the manufacturer’s instructions. Statistical analysis was performed with GraphPad Prism version 5·00 (GraphPad, San Diego, CA, USA) using the appropriate statistical tests, as stated in the figure legends. To ensure the correct population of cells was accessed for whole blood analysis, total CD3+CD8+ cells were gated and used in subsequent analysis for the absence of CD28 and any additional marker (Fig. 1a). The relative frequency of CD8+CD28− Treg in RA(MTX) was significantly higher when compared with HC, OA and RA(TNFi) (Fig. 1b). The OA disease Selleck ABT 263 control

group also showed raised levels of CD8+CD28− Treg when compared with HC. Similarly, subsets expressing CD56 (Fig. 1c) and CD94 (Fig. 1d) were found to be significantly higher in RA(MTX) in comparison with HC, OA and RA(TNFi). No significant correlation was found with the disease activity score or erythrocyte sedimentation rate. A significant positive correlation was found between CD8+CD28− Treg and age in RA(MTX) (r = 0·26; P = 0·042) and RA(TNFi) (r = 0·27; P = 0·042). In parallel with the measurement of CD8+CD28− Treg ex vivo, the ability of these cells to up-regulate expression

of the alternative co-stimulatory molecules, 4-1BB, PD-1 and ICOS, was investigated. No expression of these molecules was observed prior to stimulation. Following anti-CD3 antibody stimulation http://www.selleck.co.jp/products/Rapamycin.html 4-1BB expression was up-regulated on CD8+CD28− Treg at a similar frequency in HC and RA(MTX) groups but expression was reduced significantly in RA(TNFi) (Fig. 1e). In contrast, the up-regulation of PD-1 expression on CD8+CD28− Treg varied between groups, but RA(MTX) expression was reduced significantly compared with both HC and RA(TNFi) (Fig. 1f). The expression of ICOS by CD8+CD28− Treg was found to be significantly lower in both RA(MTX) and RA(TNFi) when compared with HC (Fig. 1g). In addition, although CTLA-4 was detectable in CD4+ cells, there was no expression, intracellular or surface, by the CD8+CD28− Treg subset (data not shown). Subsequently, the phenotype of CD8+CD28− Treg was examined in paired PBMC and SFMC. The relative frequency of CD8+CD28− Treg was increased significantly in the SF of RA(MTX) (Fig. 1hA) and RA(TNFi) (Fig. 1iA). The co-expression of CD56 (Fig. 1hB) and CD94 (Fig. 1hC) by CD8+CD28− Treg in paired RA(MTX) PBMC and SFMC samples was significantly higher in the SF.

In the study, degree of renal impairment was also independently associated with high risk for SA. A retrospective review was performed at our institution

to determine the course of SA after transplantation; specifically whether SA improved with renal transplant. When crude rates of SA in transplant patients were determined and compared with those without CKD, we found a sevenfold greater likelihood for SA in the transplant population (preliminary data). A chart review of 44 renal transplant CHIR-99021 purchase patients identified with SA revealed that 25/44 patients (56.8%) had SA diagnosed after renal transplant (preliminary data). The elapsed time from transplant date to diagnostic sleep study was 2–3 years on average. Whether renal transplantation is a risk factor for SA remains a question. Immunosuppressive therapy particularly corticosteroids have been associated with cushingoid features such as weight Alvelestat nmr gain, obesity, abnormal fat distribution and development of the metabolic syndrome. In a study of cardiac transplant patients, SA was diagnosed in 36 out of 45 patients (80%) studied with polysomnography.63 Weight gain was significantly greater in transplant recipients with SA versus those without SA. Similarly, Brilakis

et al.64 found an average weight gain of 10.7 kg in 16 of the 17 heart transplant recipients that were diagnosed with SA. Weight gain, post-transplant diabetes and steroid use are all risk factors that need to be considered in the renal transplant patient. New sleep complaints in the renal transplant Nintedanib (BIBF 1120) patient should immediately raise

awareness for SA. Immunosuppressant protocols with avoidance of steroids should be considered that may decrease risk of weight gain and volume retention. Lifestyle modifications stressing weight control should be encouraged. Conversely, a repeat sleep study should be considered in patients who had SA before transplantation as SA may be potentially cured post-operatively. Sleep apnoea is receiving more attention because of its implications on many different organ systems such as the endocrine, cardiovascular, cerebrovascular and psychosocial systems. The prevalence may be higher than previously thought because the diagnosis is increasing in frequency as physicians are becoming more aware of the disease and its implications.65 Identification and treatment of SA is important because of the potential impact on both morbidity and mortality. Chronic kidney disease appears to be associated with SA throughout all its stages, even after renal transplantation. Whether there is a direct causal relationship or whether the two diseases occur together as epiphenomena is yet to be elucidated. Studies suggest that the high prevalence of SA in ESRD may be a manifestation of uraemia and other complications from advanced renal failure such as volume overload and metabolic derangements. The association is less clear in earlier CKD.

infantum[14], have been reported previously to down-regulate CD1a expression. L. donovani was also shown to prevent activation of CD1-restricted T cells by DCs, which may represent a survival strategy by avoiding parasite glycolipid recognition [12]. L. amazonensis check details was able to alter DC differentiation by inducing a significant decrease in CD1a and CD80 expression and a significant increase in CD86 expression, causing down-regulation of the Th1 adaptive immune response [16]. We did not observe significant down-regulation of CD80 or increase of CD86. This could

be attributed to differences in the biology of Lm and L. amazonensis. In the last part of our work we showed that, despite their intracellular location, Lm clones did not stimulate IL-12p70, TNF-α or IL-10

production by DCs. In agreement with our results, others have reported that the uptake of the parasites alone by immature DCs provided an insufficient stimulus for cytokine production [6,11–13,25]. However, in the presence of an appropriate co-stimulation, and depending on the life stage and species involved, Leishmania parasites were shown to be able to modulate cytokine production by human DCs. We showed that, independently of their virulence, Lm clones were able to induce a decrease of IL-12p70 secretion during LPS-induced maturation of DC. Interestingly, although the LV Lm clone Selleckchem JNK inhibitor was not internalized by DCs, it was able to down-regulate IL-12p70 production during DC maturation similarly to the high virulent clone. It has been suggested that Leishmania-induced maturation does not require infection of DC and that direct recognition of parasites by DCs could be sufficient [28]. In agreement with our data, altered DC responsiveness to exogenous stimuli in the presence of Leishmania parasites and antigens has been reported by others [12,16,25]. L. donovani parasites Selleck Y 27632 and

excreted–secreted antigens from L. donovani and Lm inhibited strongly IL-12p70 secretion by mature DCs [25]. Leishmania phosphoglycans family of virulence-associated antigens were able to inhibit DC maturation [29]. Conversely, it was reported that Lm was able to prime DC for CD40L-dependent IL-12p70 production [6,11,30] in a life stage and species- and strain-dependent manner [11]. This variability of Leishmania parasites ability to modulate a human DCs cytokine response could be explained not only by intrinsic differences between Leishmania species or strains or infective stage, but also by differences in the specific culture conditions such as the nature of priming and triggering signals used to induce maturation.

1, ezrin, radixin and moesin) with three subdomains (F1, F2, F3), which binds integrin cytoplasmic tails (Fig. 1) and a large C-terminal rod domain that binds actin.66,67 The F3 subdomain contains a phosphotyrosine-binding

(PTB) domain that binds the integrin β subunit tail at the membrane-proximal NXXY site.67 Talin is enriched at the leading edge of chemokine-stimulated lymphocytes and in the immunological synapse together with LFA-1, vinculin this website and F-actin.68 Hence, talin acts as a bridge to link the extracellular matrix and the actin skeletal network. Kindlin is another essential player that binds differently to the integrin β subunit tail at the membrane-distal NXXY site and activates integrin (Fig. 1). Kindlin is named after the Kindler syndrome which is a kind of skin blistering disease caused by a kindlin-1 gene mutation.69 The kindlin family has three members, including kindlin-1 (Unc-112-related protein 1, URP1), kindlin-2 (Mig2) and

kindlin-3 (URP-2), which all have a conserved FERM domain composed of four subdomains. Among them, kindlin-3 is expressed exclusively in cells of haematopoietic origin. The FERM subdomain 2 in kindlin-3 is featured by a pleckstrin homology domain that is involved in membrane binding,70 and subdomain 3 in kindlin-3, which binds the Sirolimus cost distal motif of integrin β1, β2 and β3 tails.71–73 Mutations in kindlin-3 result in defective

DOK2 integrin activation in leucocytes and platelets and lead to leucocyte adhesion deficiency III.74 Kindlins are not sufficient to induce integrins to a high-affinity state, but they can promote the binding of talins to integrin tails. Talin is also not sufficient to increase integrin affinity without the aid of kindlin. Other actin-associated proteins have also been identified to interact with integrins. Paxillin is a cytoskeletal phosphotyrosine-containing protein and binds directly to the cytoplamic domain of integrin α4.75 The interaction is regulated in a protein kinase A-dependent manner. Phosphorylation of the α4 cytoplasmic domain at serine988 leads to release of paxillin from integrin.76 It mediates initial capture and rolling interactions during leucocyte migration on vascular cell adhesion molecule 1-expressing and mucosal addressin cell adhesion molecule-1-expressing vascular endothelium.77 Integrins play many essential roles in leucocytes and many key players in both ‘inside-out’ and ‘outside-in’ pathways have been well characterized since the middle 1980s. However, challenging questions remain. One major question is how different integrins coordinate with other surface receptors in different cell types to regulate cellular functions when responding to various agonists including antigens, chemokines, selectins and others.

Most of these studies are limited to DS patients who have presented with recurrent infections, and they may not represent the general DS population; however, Kuester et al. [30] reported lymphocyte

subsets of 95 DS children visiting their centre for follow-up of their thyroid function and 77% of patients had frequent respiratory infections. In this cohort, 57 (60%) of the children were aged 5–16 years, and only three children were above 16 years of age. The number and percentage of naive T cells were decreased approximately by half across the age-ranges compared to non-DS children, although they did not reach severe immunodeficiency levels. For example, the median naive CD4 T cells in 5–10-year-old children was 280 cells/µl (44% of CD4 T cells) MK-1775 research buy for DS and 730 cells/µl (72% of CD4 T cells) for age-matched controls. There was no association of low T cell counts and the presence of recurrent infections. Memory T cell percentage and count were not significantly different from normal controls, an argument that the study authors used to postulate the presence of an intrinsic immune defect that renders those cells impaired to control infections. In the same DS cohort, the investigators compared several maturation stages of peripheral blood B cells with those of normal children and found decreased numbers of all B cell stages, particularly

naive B cells [31]. There was no statistically significant CH5424802 research buy association of low B cell counts and clinical conditions. T cell and B cell function have been examined in DS. The lymphocyte proliferative response to phytohaemagglutinin has been reported to be significantly low in DS [8,32]. The abnormalities in immunoglobulin (Ig)G levels do not occur in all DS subjects; while

some DS children present with IgG levels under normal ranges for age, particularly IgG2 [8], most DS subjects show adequate levels [33]. In a cohort of 26 DS children, of whom 18 had increased rate of infections, only one child had decreased IgG2 levels [34]. An older cohort of DS individuals, with a mean age of 55 years, showed significantly higher levels of IgG1 and decreased levels of IgG2 subclasses compared to age-matched individuals Evodiamine [35]. The high frequency of periodontal disease in DS might be explained in part by a deficiency of IgA in saliva of DS individuals. A study of young and older adults with DS demonstrated a drastic reduction of both total IgA concentration in saliva and specific IgA to common oral pathogens, compared to controls [36]. The specific antibody responses of DS children to several immunizations have been found defective, although most develop protective IgG titres. Lopez et al. [37] showed that the specific IgG titres to the neoantigen bacteriophage phi174 in DS children were lower than the normal range. Hawkes et al.

1a–c). Maximal levels of expression were detected at 24 h for MIP-1α and at 6 h for MIP-1β and RANTES following Tax1 treatment. Interestingly, higher levels of MIP-1α were observed at 6 and 12 h when PBMCs were treated with Tax2A compared to Tax1 (Fig. 1a), while higher levels of MIP-1β and RANTES were detected after 3 and 6 h for Tax1 treatment compared to Tax2A (Fig. 1b,c).

These results indicated that HTLV-2 Tax protein induced a rapid and sustained production of MIP-1α, MIP-1β and RANTES. Tax1 and Tax2A recombinant proteins were assessed for their potential to activate the p65/RelA subunit, which is a well-established indicator of the canonical NF-κB pathway [34], a rapid-acting primary transcription factor. We also employed Tax2A/1–198 and Tax2A/135–331 recombinant Tax2A fragments containing NF-κB domains [28, 29] to evaluate their Talazoparib potential to activate the NF-κB pathway compared to the entire Tax2A protein. Treated cells were immunolabelled

for the detection of phosphorylated p65/RelA by immunofluorescence. After 1 h, both the entire RGFP966 research buy Tax2A and the Tax2A/1–198 fragment induced p65/RelA activation significantly over controls (14- and 10-fold, respectively, P < 0·05) (Fig. 2a). Significantly higher levels of activation were also observed when the entire Tax2A and the Tax2A/135–331 fragment were used to treat PBMCs for 2 h (27- and ninefold, respectively, P < 0·05). The complete Tax2A protein also induced significantly higher levels of p65/RelA activation compared to Tax1 and both Tax2A fragments after 2 h of treatment (Fig. 2b). Tax1 protein induced significant levels of p65/RelA activation at 1 (12-fold) and 2 h (eightfold) (P < 0·05). The Jurkat cell Thymidylate synthase line served as a negative control and the HTLV-2-infected MoT cell line, displaying constitutive activation of NF-κB [27], served as positive control in the assay (Fig. 2c). It was observed that the activation of p65/RelA (Fig. 2a,b) by Tax2A preceded the secretion of MIP-1α, MIP-1β and RANTES in all conditions tested (Fig. 1). Next, the

binding activity of p65/RelA and p50 NF-κB subunits was assessed quantitatively in nuclear extracts from PBMCs treated with Tax2A or Tax1 proteins using the TransAM assay. Tax2A significantly enhanced the activation of both p65/RelA and p50 after 1 and 2 h compared to untreated and mock-treated controls (P < 0·001). Although Tax1 also induced high levels of both p65 and p50 activation by 1 (P < 0·05) and 2 h (P < 0·001) after treatment compared to controls (Fig. 3a,c), Tax2A induced significantly higher levels of p65/RelA activation than Tax1 following 1 h of treatment (P < 0·05) (Fig. 3a). Nuclear extracts from MoT and Raji nuclear extracts, used as positive controls, induced high levels of both p65/RelA and p50 activation (Fig. 3b,d).

Under these circumstances it is highly likely that presentation of autoantigen also takes place in the joint. Therefore, it could be speculated that, in RA, tolDC would ideally have the ability to act in several locations: in the rheumatoid joint to anergize autoantigen-specific effector T cells locally, and in the draining lymph node to

induce Tregs from autoantigen-specific naive T cells. However, it should be noted that T cells from RA patients can be resistant to at least some tolerogenic signals; for instance, they can resist selleck chemicals IL-10- and IDO-mediated suppression [90, 91]. Our tolDC operate, at least partially, via a TGF-β-dependent mechanism and inhibit proliferation and IFN-γ production of peripheral blood RA T cells in vitro (unpublished data); however, whether they can inhibit autoreactive T cells in the rheumatoid joint remains to be determined. Despite the fact that our tolDC have similar ability as mature DC to process and present exogenous antigen, tolDC have lower T cell stimulatory capacity than mature DC, in line with their lower expression of co-stimulatory molecules and low production of proinflammatory cytokines [55, 82]. Moreover, tolDC induce hyporesponsiveness (‘anergy’) in antigen-experienced memory T cells while

polarizing naive T cells towards an anti-inflammatory cytokine profile [55]. We have also shown that, in a mouse in-vivo model Calpain of collagen-induced arthritis, murine bone marrow-derived tolDC generated with Dex, VitD3 and LPS have a therapeutic effect: treatment learn more of arthritic mice with tolDC (1 million cells injected intravenously three times over 8 days) reduced significantly the severity and progression of arthritis, whereas treatment with immunogenic mature DC did not reduce disease and, in fact, exacerbated arthritis [49]. Interestingly, tolDC exerted a therapeutic effect only if they had been loaded with the immunizing antigen, type

II collagen. Treatment with tolDC was associated with a reduction in Th17 cells and an enhancement of IL-10-producing T cells, and a reduction in type II collagen-specific T cell proliferation, possibly explaining their therapeutic effect. Thus, this type of tolDC is a potentially powerful tool for the treatment of RA and other autoimmune diseases. Before tolDC can be applied in a clinical trial, a protocol to generate clinical grade tolDC, compliant with current good manufacturing practice (cGMP) regulations, had to be established. For this purpose, the research-grade fetal calf serum (FCS)-containing medium was replaced with cGMP-grade medium specialized for DC (CellGro® DC medium from CellGenix, Freiburg, Germany) and LPS was replaced with MPLA, a synthetic cGMP-grade TLR-4 ligand (from Avanti Polar Lipids, Alabaster, AL, USA).

We describe a systemic inflammatory response in human fetuses born to mothers with evidence of maternal anti-fetal rejection. The transcriptome and proteome of this novel type Poziotinib nmr of fetal inflammatory response were different from that of FIRS type I (which is associated with acute infection/inflammation). “
“Control of intracellular

Salmonella infection requires Th1 priming and IFN-γ production. Here, we show that efficient Th1 priming after Salmonella infection requires CD11c+CD11bhiF4/80+ monocyte-derived dendritic cells (moDCs). In non-infected spleens, moDCs are absent from T-cell zones (T zones) of secondary lymphoid tissues, but by 24 h post-infection moDCs are readily discernible in these sites. The accumulation of moDCs is more dependent upon

bacterial viability than bacterial virulence. Kinetic studies showed that moDCs were necessary to prime but not sustain Th1 responses, while ex vivo studies showed that antigen-experienced moDCs were sufficient to induce T-cell proliferation and IFN-γ production via a TNF-α-dependent mechanism. Importantly, moDCs and cDCs when co-cultured induced superior Th1 differentiation than either subset alone, and this activity was independent of TNF-α. Thus, optimal Th1 development to Salmonella requires the rapid accumulation of moDCs within T zones and their collaboration with cDCs. Adaptive Th1 responses Ceritinib cost are important for resolving intracellular bacterial infections such as those caused by Salmonella and Mycobacteria. Priming of CD4+ T cells occurs within the T-cell zones (T zones) of secondary lymphoid tissues and requires cognate interaction between dendritic cells (DCs) and naive CD4+ T cells 1. After priming, T cells upregulate Fossariinae CD69 and CD44 and downregulate L-selectin (CD62L) and begin to proliferate. These events

occur rapidly after Salmonella Typhimurium infection (STm) 2 and are detectable within the first 24 h. In parallel, T cells can acquire Th1 features such as the capacity to produce IFN-γ 3. In the absence of Th1 differentiation and IFN-γ production, clearance of STm infections is markedly impaired and infection is more disseminated 4–10. DCs are the most potent APCs. As immature cells, DCs are strategically located in non-lymphoid tissues where they are likely to encounter antigen. After antigen encounter, DCs migrate to the T zones of secondary lymphoid tissues to present it to naive T cells. In secondary lymphoid tissues, in the steady state, several populations of resident DCs can be found and the role of these cells in priming T-cell responses has been studied 11, 12. Importantly, during infection or inflammation, another population of DCs differentiate from recruited blood monocytes. 13–16. These cells, monocyte-derived DCs (moDCs), are characterized by lower expression of CD11c than resident, conventional DCs (cDCs), yet they maintain monocyte markers such as CD115, Ly-6C and CD11b.

In this section, we will discuss the pathological role of the STAT3 pathway and STAT6 pathway in M2-like TAM polarization, and the pharmacological effects of the agents that inhibit these pathways. Several other pathways and M2 targeting agents will be outlined at the end of this section. STAT3 is consistently active in many tumours and acts as a negative regulator for macrophage activation and the host’s inflammatory responses.[120] When the activation of STAT3 was blocked, either with a dominant negative variant or an antisense oligonucleotide, macrophages could increase

the release of IL-12 and RANTES and reverse the systemic immune tolerance.[121] Now, some STAT3 inhibitors are under investigation. For instance, a small molecular inhibitor of STAT3 (WP1066) was found to reverse immune tolerance in patients with malignant glioma, correlating with selectively Selleck 3-MA induced expressions of co-stimulatory molecules (CD80 and CD86) on peripheral macrophages and tumour-infiltrating microglias, and immune-stimulatory cytokines (e.g. IL-12).[122] Two clinical tyrosine kinase inhibitors (sunitinib and sorafenib) have shown their inhibitory

effects on STAT3 in macrophages in vitro.[123, 124] Sorafenib can restore IL-12 production but suppress IL-10 expression in prostaglandin E2 conditioned macrophages, indicating its effects on reversing the immunosuppressive cytokine profile of TAMs.[124] Moreover, two newly identified inhibitors of M2 differentiation are corosolic acid and oleanolic RG7204 chemical structure acid. They can also suppress the activation Histone demethylase of STAT3.[125, 126] Actually, other novel STAT3 inhibitors, such as STA-21, IS3 295 and S3I-M2001, have been found to be efficient against tumours,[127] although their association with TAM re-polarization needs to

be shown. Another STAT family member important for TAM biology is STAT6. In one study, STAT6–/– mice produced predominantly M1-like tumoricidal TAMs with arginaselow and NOhigh, and > 60% of STAT6–/– mice rejected tumour metastasis.[128] Currently, at least three STAT6 inhibitors (AS1517499, leflunomide and TMC-264) have been identified. But their actions as modulators of TAMs remain to be clarified. Instead, several up-/down-stream mediators of STAT6 are more impressive because they could act as modulators of TAM function. These modulators include phosphatidylinositol 3-kinase (PI3K), Src homology 2-containing inositol-5′-phosphatase (SHIP), Krüppel-like factor 4 (KLF4) and c-Myc. PI3K positively regulates STAT6 activation in macrophages, whereas SHIP negatively regulates PI3K. Either PI3K inhibition or SHIP over-expression has been found to decrease the activity of the STAT6 pathway and to reduce M2 skewing of macrophages.[129] Therefore, the agents that are able to inhibit PI3K or stabilize SHIP activity may be therapeutic adjuvants for cancer. KLF4 is another interesting modulator protein of STAT6. Liao et al.[130] reported that the expression of KLF4 was induced in M2 macrophages and reduced in M1 macrophages.