Role In Macrophage Infiltration Research Articles

Identification of renal ischemia reperfusion injury-characteristic genes, pathways and immunological micro-environment features through bioinformatics approaches.

Biomarkers and pathways associated with renal ischemia reperfusion injury (IRI) had not been well unveiled. This study was intended to investigate and summarize the regulatory networks for related hub genes. Besides, the immunological micro-environment features were evaluated and the correlations between immune cells and hub genes were also explored. GSE98622 containing mouse samples with multiple IRI stages and controls was collected from the GEO database. Differentially expressed genes (DEGs) were recognized by the R package limma, and the GO and KEGG analyses were conducted by DAVID. Gene set variation analysis (GSVA) and weighted gene coexpression network analysis (WGCNA) had been implemented to uncover changed pathways and gene modules related to IRI. Besides the known pathways such as apoptosis pathway, metabolic pathway, and cell cycle pathways, some novel pathways were also discovered to be critical in IRI. A series of novel genes associated with IRI was also dug out. An IRI mouse model was constructed to validate the results. The well-known IRI marker genes (Kim1 and Lcn2) and novel hub genes (Hbegf, Serpine2, Apbb1ip, Trip13, Atf3, and Ncaph) had been proved by the quantitative real-time polymerase chain reaction (qRT-PCR). Thereafter, miRNAs targeted to the dysregulated genes were predicted and the miRNA-target network was constructed. Furthermore, the immune infiltration for these samples was predicted and the results showed that macrophages infiltrated to the injured kidney to affect the tissue repair or fibrosis. Hub genes were significantly positively or negatively correlated with the macrophage abundance indicating they played a crucial role in macrophage infiltration. Consequently, the pathways, hub genes, miRNAs, and the immune microenvironment may explain the mechanism of IRI and might be the potential targets for IRI treatments.

Unraveling the role of galectin-3 in cardiac pathology and physiology.

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging.

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment.

Inflammatory mediators and inflammatory cells in the inflammatory microenvironment promote the transformation of normal cells to cancer cells in the early stage of cancer, promote the growth and development of cancer cells, and induce tumor immune escape. The monomeric active ingredient β-elemene is extracted from the traditional Chinese medicine Curcuma wenyujin and has been proven to have good anti-inflammatory and antitumor activities in clinical applications for more than 20 years in China. Recent studies have found that this traditional Chinese medicine plays a vital role in macrophage infiltration and M2 polarization, as well as in regulating immune disorders, and it even regulates the transcription factors NF-κB and STAT3 to alter inflammation, tumorigenesis, and development. In addition, β-elemene regulates not only different inflammatory factors (such as TNF-α, IFN, TGF-β, and IL-6/10) but also oxidative stress in vivo and in vitro. The excellent anti-inflammatory and antitumor effects of β-elemene and its ability to alter the inflammatory microenvironment of tumors have been gradually elaborated. Although the study of monomeric active ingredients in traditional Chinese medicines is insufficient in terms of quality and quantity, the pharmacological effects of more active ingredients of traditional Chinese medicines will be revealed after β-elemene.

Effect of Lifestyle Modification with Metformin on Serum Chemerin Concentration of Metabolic Syndrome Subjects

Chemerin is adipokine that plays an important role in macrophage infiltration into adipose tissue and may contribute to inflammation development and insulin resistance. This study aimed to determine the effect of lifestyle modification with and without metformin on chemerin in metabolic syndrome. Forty-five metabolic syndrome subjects (IDF-2005) were randomly assigned to one of the two groups: placebo group (n=22) and metformin group (n=23). Both groups underwent a 12-week lifestyle modification (diet and moderate aerobic-exercise). Only 40 participants (placebo group n=20 and metformin group n=20) completed the survey whereas 5 participants dropped out of the study. After their lifestyle was modified, body weight, BMI, WC, and chemerin decreased significantly (p<0.001) in both groups. Moreover, there was a significant difference between both groups in body weight, BMI, and WC (p<0.05) but not for chemerin. Thus, lifestyle modification with metformin improved BW, BMI, WC on metabolic syndrome, and there was no decrease significantly of chemerin between placebo and metformin groups. Further investigations should be done to confirm the effect of lifestyle modification and metformin on chemerin after an extended follow-up period.

Resveratrol reduces the inflammatory response in adipose tissue and improves adipose insulin signaling in high-fat diet-fed mice.

BackgroundObesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice.MethodsA total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT.ResultsHFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT.ConclusionOur results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma.

Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages in vitro, but intratumoral macrophage infiltration was not decreased by PLX3397 in vivo Gene expression profiling of tumor-associated macrophages (TAM) showed that TAMs from the PLX3397-treated tumors were polarized toward an M1-like phenotype compared with those from vehicle-treated tumors. In addition, PLX3397 treatment increased CD8+ T-cell infiltration, whereas CD4+ T-cell infiltration was decreased. Further study revealed that tumor cell-derived CSF-2 protected TAMs from being depleted by PLX3397. In conclusion, CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs. CSF-1R blockade warrants further investigation in the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1544-54. ©2017 AACR.

Administration of Lactobacillus gasseri SBT2055 suppresses macrophage infiltration into adipose tissue in diet-induced obese mice.

Administration of Lactobacillus gasseri SBT2055 (LG2055) has been shown to prevent body weight gain and it also down-regulates the expression of the Ccl2 gene in adipose tissue in diet-induced obese mice. The CC chemokine ligand 2 has a crucial role in macrophage infiltration into adipose tissue, which is known to exacerbate inflammation. However, it is not yet known how LG2055 affects the invasion of macrophages into adipose tissue. C57BL/6J male mice were fed a normal-fat diet (10 % energy fat), high-fat diet (HFD; 45 % energy fat), or HFD containing LG2055 for 12 weeks. After the feeding period, gene expression and macrophage population in adipose tissue were analysed by real-time PCR and flow cytometry, respectively. Body weight and abdominal fat weight were not altered by feeding LG2055. Flow cytometry analysis revealed that the population of macrophages in adipose tissue was significantly reduced by feeding LG2055 compared with HFD only. Furthermore, the ratio of classically activated inflammatory macrophages (M1 macrophages) to total macrophages was significantly decreased in the LG2055-fed group. The expressions of Ccl2, Ccr2 and Lep were down-regulated and that of Il6, Tnf and Nos2 tended to be down-regulated in adipose tissue by feeding LG2055. In addition, fasting glucose levels were significantly decreased in the LG2055-fed group. These data suggest that administration of LG2055 might attenuate inflammation, which is caused by the intake of an HFD, through the inhibition of macrophage invasion into adipose tissue.

Somatostatin Derivate (smsDX) Attenuates the TAM-Stimulated Proliferation, Migration and Invasion of Prostate Cancer via NF-κB Regulation.

Tumor development and progression are influenced by macrophages of the surrounding microenvironment. To investigate the influences of an inflammatory tumor microenvironment on the growth and metastasis of prostate cancer, the present study used a co-culture model of prostate cancer (PCa) cells with tumor-associated macrophage (TAM)-conditioned medium (MCM). MCM promoted PCa cell (LNCaP, DU145 and PC-3) growth, and a xenograft model in nude mice consistently demonstrated that MCM could promote tumor growth. MCM also stimulated migration and invasion in vitro. Somatostatin derivate (smsDX) significantly attenuated the TAM-stimulated proliferation, migration and invasion of prostate cancer. Immunohistochemistry revealed that NF-κB was over-expressed in PCa and BPH with chronic inflammatory tissue specimens and was positively correlated with macrophage infiltration. Further investigation into the underlying mechanism revealed that NF-κB played an important role in macrophage infiltration. SmsDX inhibited the paracrine loop between TAM and PCa cells and may represent a potential therapeutic agent for PCa.

Osteopontin – a multifunctional protein and its impact on an insulin resistance development

Osteopontin (OPN) is one of the many physiological elements creating human musculoskeletal system. It is suspected that this protein is one of the most important mediators responsible for osseous tissue mass resorption, regulated by parthormon. The origin of its name comes from one of its physiological action – rebuilding of the bone mass structure (osteo – bone, pontin – bridge). Osteopontin fulfils many different actions being secreted by many different types of cells, including macrophages, lymphocytes, epithelial cells, vascular smooth muscle cells, and osteoblasts. OPN plays an important part in inflammatory process. It provokes macrophages and dendritic cells to movement into the destination where inflammatory process takes place. It also stimulates macrophages to interleukin 12 (IL12) and interferon ? (IFN ?) secretion. Increased OPN concentration in blood stream might be regarded as a novel, independent indicator of coronary artery disease. Osteopontin plays an important role in macrophage infiltration of the adipose tissue and at the same time contributes to insulin resistance. Obesity induces chronic, low-grade tissue inflammation. Positive correlation was observed between body mass index (BMI) and number of macrophages accumulated in the fat tissue. Once aroused monocytes infiltrate the adipose tissue, which leads to persisting chronic inflammation. At the same time the excreted by them cytokines may be connected with the mechanisms of obesity-induced insulin resistance.

Hemin Therapy Improves Kidney Function in Male Streptozotocin-Induced Diabetic Rats: Role of the Heme Oxygenase/Atrial Natriuretic Peptide/Adiponectin Axis

Diabetic nephropathy is characterized by elevated macrophage infiltration and inflammation. Although heme-oxygenase (HO) is cytoprotective, its role in macrophage infiltration and nephropathy in type 1 diabetes is not completely elucidated. Administering the HO inducer, hemin, to streptozotocin-diabetic rats suppressed renal proinflammatory macrophage-M1 phenotype alongside several proinflammatory agents, chemokines, and cytokines including macrophage inflammatory protein 1α (MIP-1α), macrophage-chemoattractant protein-1 (MCP-1), TNF-α, IL-1β, IL-6, nuclear factor-κB (NF-κB), and aldosterone, a stimulator of the inflammatory/oxidative transcription factor, NF-κB. Similarly, hemin therapy attenuated extracellular matrix/profibrotic proteins implicated in renal injury including fibronectin, collagen-IV, and TGF-β1 and reduced several renal histopathological lesions such as glomerulosclerosis, tubular necrosis, tubular vacuolization, and interstitial macrophage infiltration. Furthermore, hemin reduced markers of kidney dysfunction like proteinuria and albuminuria but increased creatinine clearance, suggesting improved kidney function. Correspondingly, hemin significantly enhanced the antiinflammatory macrophage-M2 phenotype, IL-10, adiponectin, HO-1, HO activity, and atrial natriuretic-peptide (ANP), a substance that abates TNF-α, IL-6, and IL-1β, with parallel increase of urinary cGMP, a surrogate marker of ANP. Contrarily, coadministering the HO inhibitor, chromium-mesoporphyrin with the HO-inducer, hemin nullified the antidiabetic and renoprotective effects, whereas administering chromium-mesoporphyrin alone abrogated basal HO activity, reduced basal adiponectin and ANP levels, aggravated hyperglycemia, and further increased MCP-1, MIP-1α, aldosterone, NF-κB, TNF-α, IL-6, IL-1β, proteinuria/albuminuria, and aggravated creatinine clearance, thus exacerbating renal dysfunction, suggesting the importance of the basal HO-adiponectin-ANP axis in renoprotection and kidney function. Collectively, these data suggest that hemin ameliorates diabetic nephropathy by selectively enhancing the antiinflammatory macrophage-M2 phenotype and IL-10 while concomitantly abating the proinflammatory macrophage-M1 phenotype and suppressing extracellular matrix/profibrotic factors with reduction of renal lesions including interstitial macrophage infiltration. Because aldosterone stimulate NF-κB, which activates cytokines like TNF-α, IL-6, IL-1β that in turn stimulate chemokines such as MCP-1 and MIP-1α to promote macrophage-M1 infiltration, the hemin-dependent potentiation of the HO-adiponectin-ANP axis may account for reduced macrophage infiltration and inflammatory insults in streptozotocin-diabetic rats.

Macrophage elastase (MMP-12) in expanding murine adipose tissue

BackgroundMatrix metalloproteinases (MMPs) are known to play a role in adipose tissue development, but little information is available on the role of individual proteinases. Expansion of adipose tissue is associated with an increased macrophage content. Macrophage elastase (MMP-12) has an important role in macrophage infiltration, which induces pro-inflammatory effects in adipose tissue. MethodsThe role of MMP-12 was investigated in adipose tissues of MMP-12 deficient and wild-type control mice kept on normal chow or on high fat diet for 15weeks. ResultsMMP-12 deficiency had no significant effect on total body weight or on subcutaneous (SC) or gonadal (GON) adipose tissue mass. Adipocyte and blood vessel size and density in SC and GON adipose tissues of obese mice were also comparable in MMP-12 deficient and control mice. Macrophage infiltration in SC and GON adipose tissues was not affected by MMP-12 deficiency, but the amount of crown-like structures (CLS) was significantly lower. MMP-12 deficiency did not affect elastin content in the extracellular matrix of SC or GON adipose tissue. ConclusionsAdipose tissue mass and composition in mice with nutritionally induced obesity was not markedly affected by MMP-12 deficiency, except for an apparently lower degree of CLS. General SignificanceMMP-12 does not seem to be essential for macrophage infiltration in adipose tissue, but contributes to the formation of CLS surrounding moribund adipocytes.

Twelve-Week Aerobic Training Decreases Chemerin Level and Improves Cardiometabolic Risk Factors in Overweight and Obese Men

The inflammatory state of adipose tissue in obese subjects may be the most important factor linking increased adipose tissue mass to insulin resistance. Chemerin is a newly discovered adipokine that plays an important role in macrophage infiltration into adipose tissue and may contribute to the development of inflammation and insulin resistance. We examined the effects of 12 weeks of aerobic training on serum chemerin levels in association with cardiovascular risk factors in overweight and obese males. Twenty-one overweight and obese subjects [44.3 (±4.1 yrs, body mass index (BMI) ≥25 kg/m(2)) were assigned to exercise training (obese EX, n= 11) and control (obese CON, n= 10) groups. The obese EX group participated in 12 weeks of progressive aerobic training 5 days a week. Serum chemerin, insulin resistance, lipid profiles, blood pressure, and body composition were all measured before and after the training. After the aerobic training, waist circumference (P=0.009), fat percent (P=0.03), visceral fat (P=0.03), subcutaneous fat (P=0.01), fasting glucose (P=0.01), insulin resistance (P=0.03), triglyceride (P=0.05), total cholesterol (P=0.04), low-density lipoprotein cholesterol (P=0.05) and systolic blood pressure (P=0.04) of participates were significantly decreased. Concurrently, serum chemerin concentrations were significantly decreased after aerobic program (P=0.02). Aerobic training caused an improvement in cardiometabolic risk factors in obese subjects, and this improvement was accompanied by decreased chemerin levels.

Role of CC Chemokine Receptor 2 in Bone Marrow Cells in the Recruitment of Macrophages into Obese Adipose Tissue

The MCP-1 (monocyte chemoattractant protein-1)/CCR2 (CC motif chemokine receptor-2) pathway may play a role in macrophage infiltration into obese adipose tissue. Here we investigated the role of CCR2 in the recruitment of bone marrow-derived macrophages into obese adipose tissue in vitro and in vivo. Using the TAXIScan device, which can measure quantitatively the directionality and velocity of cell migration at time lapse intervals in vitro, we demonstrated that bone marrow cells (BMCs) from wild type mice migrate directly toward MCP-1 or culture medium conditioned by adipose tissue explants of genetically obese ob/ob mice, which are efficiently suppressed by pharmacological blockade of CCR2 signaling. The number of F4/80-positive macrophages was reduced in the adipose tissue from high fat diet-fed obese KKAy or ob/ob mice treated with a CCR2 antagonist propagermanium relative to vehicle-treated groups. We also found that the number of macrophages is reduced in the adipose tissue from ob/ob mice reconstituted with CCR2(-/-) BMCs (ob/ob + CCR2(-/-) BMCs) relative to those with CCR2+/+ BMCs (ob/ob + CCR2+/+ BMCs). Expression of mRNAs for CD11c and TLR4 (Toll-like receptor 4) markers of proinflammatory M1 macrophages was also decreased in the adipose tissue from ob/ob + CCR2(-/-) BMCs relative to ob/ob + CCR2+/+ BMCs, whereas mannose receptor and CD163, markers of anti-inflammatory M2 macrophages, were unchanged. This study provides in vivo and in vitro evidence that CCR2 in bone marrow cells plays an important role in the recruitment of macrophages into obese adipose tissue.

Abstract 3390: Impairment of Post-ischemic Neovascularization in Mice Lacking IQGAP1, an Actin-binding Scaffold Protein: Role in Macrophage Infiltration and ROS production

Neovascularization is important repair mechanism in response to ischemic injury and its process is in part dependent on reactive oxygen species (ROS). IQGAP1, an actin-binding scaffold protein, is key regulator for actin cytoskeleton and motility. We demonstrated that IQGAP1 is expressed in endothelial cells (ECs) and mediates VEGF-induced ROS production and migration of cultured ECs. However, its role in postnatal neovascularization is unknown. Here we show that neovascularization induced by hindlimb ischemia is significantly inhibited in IQGAP1-deficient mice as evaluated by laser Doppler blood flow (38%), capillary density (48%) and alpha-actin positive arterioles (68%). In wild-type (WT) mice, western and immunofluorescence analysis reveal that IQGAP1 protein expression in ischemic tissues is significantly increased at Mac3+ macrophages and lectin+ capillary-like ECs at 3 days and 7 days after ischemia, respectively, which is associated with increased superoxide production. Of note, macrophage infiltration is important for post-ischemic revascularization. Mice lacking IQGAP1 show significant decrease in the number of infiltrated Mac3-positive macrophage and superoxide production in ischemic muscles (30% and 52%, respectively) as compared to WT mice. Numbers of inflammatory cells and cKit+/Flk1+ endothelial progenitor cells in peripheral blood are not affected in these knockout mice. Moreover, thioglycollate-induced peritoneal leukocyte recruitment and accumulation are significantly inhibited in IQGAP1-deficient mice (53%), whereas white blood cell number is not changed. In vitro, peritonitis-elicited (activated) macrophages obtained from IQGAP1-deficient mice show impaired polarization of actin, as visualized by phalloidin staining as well as complete inhibition of migration towards stromal derived factor-1 and VEGF, as measured by modified Boyden-chambered method. In summary, IQGAP1 plays a key role in reparative neovascularization in response to tissue ischemia by regulating not only ECs but also macrophage migration/infiltration as well as ROS production in the vessel growth area. Thus, IQGAP1 is a potential therapeutic target to promote neovascularization in ischemic cardiovascular diseases. This research has received full or partial funding support from the American Heart Association, AHA National Center.

Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy

Monocyte chemoattractant protein-1 (MCP-1), an important chemokine whose expression is increased during the course of obesity, plays a role in macrophage infiltration into obese adipose tissue. This study was designed to elucidate the role of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) in the induction of MCP-1 during the course of adipocyte hypertrophy. We examined the time course of MKP-1 and MCP-1 mRNA expression and extracellular signal-regulated kinase (ERK) phosphorylation in the adipose tissue from mice rendered mildly obese by a short term high fat diet. We also studied the role of MKP-1 in the induction of MCP-1 in 3T3-L1 adipocytes during the course of adipocyte hypertrophy. MCP-1 mRNA expression was increased, followed by ERK activation and down-regulation of MKP-1, an inducible dual specificity phosphatase to inactivate ERK, in the adipose tissue at the early stage of obesity induced by a short term high fat diet, when macrophages are not infiltrated. Down-regulation of MKP-1 preceded ERK activation and increased production of MCP-1 in 3T3-L1 adipocytes in vitro during the course of adipocyte hypertrophy. Adenovirus-mediated restoration of MKP-1 in hypertrophied 3T3-L1 adipocytes reduced the otherwise increased ERK phosphorylation, thereby leading to the significant reduction of MCP-1 mRNA expression. This study provides evidence that the down-regulation of MKP-1 is critical for increased production of MCP-1 during the course of adipocyte hypertrophy.

Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy.

NF-kappaB-dependent pathways play an important role in macrophage infiltration and kidney injury. NF-kappaB is regulated by angiotensin II (AII). However, the role of this pathway in diabetic nephropathy has not been clearly delineated. First, the activation of NF-kappaB, monocyte chemoattractant protein-1 (MCP-1), and macrophage infiltration in the diabetic kidney were explored, in a temporal manner. The active subunit of NF-kappaB, p65, was elevated in the diabetic animals in association with increased MCP-1 gene expression and macrophage infiltration. Second, the effects of treatment for 4 wk with the AII type 1 receptor antagonist valsartan, the AII type 2 receptor antagonist PD123319, or pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and on these parameters were assessed. These treatments were associated with a reduction in p65 activation, MCP-1 gene expression, and macrophage infiltration. These findings demonstrate a role for activation of NF-kappaB, in particular the p65 subunit, in the pathogenesis of early renal macrophage infiltration in experimental diabetes. In the context of the known proinflammatory effects of AII, it is postulated that the renoprotection conferred by angiotensin II receptor antagonism is at least partly related to the inhibition of NF-kappaB-dependent pathways.

Expression of the chemokines, monocyte chemotactic protein (MCP)-1 and MCP-2 in endometrium of normal women and Norplant® users, does not support a central role in macrophage infiltration into endometrium

The endometrium contains many leukocytes, including macrophages, the numbers varying with the time of the menstrual cycle and being maximal peri-menstrually. The long-acting progestogenic contraceptive Norplant®, has a high rate of discontinuation due to uterine bleeding; this is associated with large numbers of endometrial macrophages. Monocyte chemotactic proteins (MCP) act to recruit and activate monocytes into sites of inflammation. This study compared the cellular localization of endometrial MCP-1 and MCP-2 across the normal menstrual cycle and in users of Norplant®. Both MCP-1 and MCP-2 were present in normal endometrium, but with very different patterns of cellular location and considerable variability between individuals. MCP-1 of epithelial origin was present in 77% of tissues, while stromal staining was present in 52% and vascular staining in 34% of samples. MCP-1 was also released from both epithelial and stromal cells in culture. MCP-2 staining was predominantly epithelial and was found in 52% of tissues while stromal staining was present in only 3/56 samples. Vascular staining of MCP-2 was found in 2/56 samples. The epithelial staining was mostly punctate and sometimes within uterine secretions. No correlation of staining for MCP-1 or -2 with the phase of the cycle was found in any cellular compartment. Very little immunoreactive MCP-1 or MCP-2 was detected in endometrium from Norplant® users regardless of morphological subtype. These distributions do not support a role for either MCP-1 or MCP-2 in the migration of macrophages into the endometrium and suggest that these cytokines may have other functions in this tissue.

Expression of monocyte chemoattractant protein-1 in meningioma.

Monocyte chemoattractant protein-1 (MCP-1), purified from glioma cell line (U-105MG) culture fluid, attracts monocytes but not neutrophils. Macrophage accumulation is one of the pathological features of meningioma. To investigate the mechanism of macrophage infiltration into meningioma, the expression and localization of MCP-1 in 16 cases of meningioma were studied using Northern blot analysis and immunohistochemistry. Seven of 16 meningiomas expressed MCP-1 messenger ribonucleic acid and protein, and some degree of macrophage infiltration was seen in all 16 meningiomas. There was a relationship between MCP-1 expression and the degree of macrophage infiltration; MCP-1 was strongly expressed in meningiomas with a high degree of macrophage infiltration. Sometimes the meningioma was accompanied by perifocal edema; a correlation between macrophage infiltration into brain tumors and perifocal edema has already been reported. It was found that the degree of MCP-1 expression is not correlated with the extent of perifocal edema. The authors' findings suggest that MCP-1 plays an important role in macrophage infiltration into meningioma.

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Two forms of monocyte chemoattractant protein-1 (MCP-1), MCP-lα and β have been purified from culture supernatants of either human malignant glioma cell line cells or PHA-stimulated peripheral blood mononuclear leukocytes. MCP-1 is chemotactic for monocytes but not for neutrophils, and appears to be identical to lymphocyte-derived chemotactic factor reported previously by others in an early era of lymphokine research. Amino acid sequence analysis and cDNA cloning have revealed that MCP-1 belongs to a family of proteins characterized by the location of 4 cysteins. Among those, mouse JE which was defined as a clone expressed by PDGF-stimulated fibroblasts has the highest similarity to MCP-1, suggesting that MCP-1 is a human homologue of mouse JE.Recently human JE has been cloned and found to be identical to MCP-1. Furthermore, human fibroblasts are capable to produce MCP-1 and the production is regulated by PDGF. From these results, it is highly possible that MCP-1 is identical to JE and this protein may play an important role in macrophage infiltration in vivo.