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Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., , , , , , , , , , and , in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. The reduced expression of downstream signaling molecules, specially and , confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

Background: Chemokines are involved in leucocyte chemotaxis. Infiltrating leucocytes play an important role of tissue injury in systemic lupus erythematosus (SLE). Objective: To investigate the role of inflammatory chemokines and their association with interleukin 18 (IL18) in SLE pathogenesis and disease activity. Methods: Plasma concentrations and ex vivo peripheral blood mononuclear cell production of inflammatory chemokines IP-10, RANTES, MIG, MCP-1, TARC, IL8, and GROα, and proinflammatory cytokines IL18, IFNγ, IL2, IL4, and IL10 were assayed in 80 SLE patients with or without renal disease and 40 healthy controls by immunofluorescence flow cytometry and enzyme linked immunosorbent assay. Results: Plasma IP10, RANTES, MIG, MCP-1, GROα, and IL18 concentrations in all SLE patients were higher than in controls, and correlated significantly with SLEDAI score (all p<0.05). In SLE patients without renal disease, IP10, RANTES, MIG, MCP-1, IL8, and IL18 correlated positively with SLEDAI score, while in those with renal derangement, IP10, IL8, IL10, and IL18 correlated with disease activity (all p<0.05). Plasma IL18 concentration correlated positively with IP10, MIG, GROα, and IL8 in all SLE patients (all p<0.005). Mitogen induced increases in ex vivo production of IP10, MCP-1, TARC, IFNγ, IL4, and IL10 were higher in all SLE patients regardless of their difference in disease activity (all p<0.05). Patients with renal disease had an augmented ex vivo release of RANTES. Conclusions: The correlation of raised plasma concentration and ex vivo production of inflammatory chemokines with disease activity, and their association with IL18, supports the view that chemotaxis of Th1/Th2 lymphocytes and neutrophils is important in SLE pathogenesis.

Hemorrhoids and fistula are considered the most common anorectal conditions in the general population. These conditions affect the quality of a patient's life by causing pain and bleeding during defecation or even in the resting state. Lower grades of hemorrhoids may be controlled by traditional measures. However, surgery is an effective treatment option in recurrent-lower and higher-grade hemorrhoids. Surgical procedures are associated with various complications, including pain and delayed wound healing. Recurrence of hemorrhoids is also a major concern in the post-operative period. An anal fistula is the connection between the anus and the skin and causes severe pain, swelling, as well as blood and pus discharge. Fistula has serious social and economic consequences. Hence, it is important to understand the pathophysiology and molecular pathology of hemorrhoids and fistula, to identify the molecular targets and to develop pharmacological-interventions. In a previous study by our group, the polyherbal formulation Anoac-H was developed for the treatment of different stages of hemorrhoids and fistula, and it was demonstrated that Anoac-H is an effective formulation for treating hemorrhoids. However, the molecular mode of action of Anoac-H on hemorrhoids and fistula had remained elusive. In the present study, it was determined that this formulation reduces the migration of mesenchymal (fibroblasts) and immune (RAW 264.7) cells without affecting their viability. It was also observed that Anoac-H suppresses the expression of regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and VEGF in fibroblasts and macrophages. Inflammation and elevated expression of RANTES and VEGF were observed in hemorrhoids and fistula. However, inflammation, as well as the expression of RANTES and VEGF, were significantly reduced in treated human hemorrhoid and fistula tissues as compared to untreated ones, confirming the in vitro results.

Background and aims: Cyclooxygenase 2 (COX-2) expression in subepithelial macrophages of colorectal adenoma has been suggested as the first in a series of steps leading to colorectal tumorigenesis. We tested the hypothesis that chemokines released from human colorectal adenoma epithelium might be involved in COX-2 expression in macrophages of the lamina propria. Methods: Endoscopic samples of sporadic colorectal adenomas were tested by enzyme linked immunosorbent assay for chemokines involved in macrophage chemotaxis. Localisation of adenoma macrophage chemoattractant protein 1 (MCP-1) and COX-2 were determined by immunohistochemistry. The effects of MCP-1, in the presence or absence of celecoxib, on COX-2 expression, and prostaglandin (PG) E2 and vascular endothelial growth factor (VEGF) release, were examined in human macrophages isolated from peripheral blood. Results: MCP-1 levels were markedly higher in adenoma with mild-moderate dysplasia (129.7 (19.9) pg/mg protein) and severe dysplasia (227.9 (35.4) pg/mg protein) than in normal colonic mucosa (55.8 (4.2) pg/mg protein). Other chemokine levels, macrophage inflammatory proteins (MIP)-1α and MIP-1β, and the chemokine regulated on activation of normal T cell expressed and secreted (RANTES) did not vary significantly between adenoma and normal mucosa. MCP-1 levels in both adenoma and normal colonic mucosa increased significantly three hours after tissue cultivation in vitro. MCP-1 immunoreactivity was restricted to the adenoma epithelium, with no reactivity seen in adjacent normal epithelial cells. MCP-1 stimulated COX-2 expression and PGE2 and VEGF release in human macrophages. Celecoxib, a selective COX-2 inhibitor, inhibited MCP-1-induced PGE2 and VEGF release in macrophages. Addition of exogenous PGE2 reversed this inhibitory effect on VEGF release, suggesting that MCP-1 in adenoma epithelial cells might be involved in COX-2 expression and subsequent macrophage activation. Conclusions: MCP-1 in colorectal adenoma epithelial cells might be involved in macrophage migration and COX-2 expression, leading to the subsequent development of colonic adenoma.

Background: Ligands of chemokine receptor CCR5, including MIP-1α, MIP-1β, and RANTES, have been implicated in rheumatoid arthritis. Objective: To test whether CCR5 d32 polymorphism has a negative association with rheumatoid arthritis in a New Zealand cohort. Methods: 516 white patients with rheumatoid arthritis and 985 healthy controls were investigated by PCR amplification of the region flanking the known CCR5 d32 deletion, and the frequencies of CCR5 d32 compared. An early rheumatoid arthritis (ERA) cohort of 92 patients was followed prospectively for two years; disease severity and outcome were correlated with CCR5 d32 status. Results: 12 control subjects (1.2%) were homozygous for d32; no d32 homozygous rheumatoid patients were detected (p = 0.012); 56 patients (10.9%) were heterozygous for the d32 polymorphism (d32/wt), compared with 169 controls (17.2%) (p = 0.0011). The CCR5 d32 allele frequency was lower in the rheumatoid patients than in the controls (frequencies of 0.054 and 0.098, respectively; p = 3.7×10−5). The frequency of CCR5 d32 did not differ significantly according to disease severity or outcome in the prospective ERA cohort, nor with HLA-DRB1 status. Conclusions: This study provides further evidence for a protective effect of the CCR5 d32 variant on rheumatoid arthritis, consistent with a role for CCR5 and its ligands in disease pathogenesis.

Marrubiin can improve blood and lymph microcirculation disturbance, and has pharmacological effects in myocardial protection, anti-inflammation and anti-oxidation. The aim of the present study was to evaluate the protective effects of marrubiin on endometriosis through suppression of the expression of regulated on activation, normal T cell expressed and secreted (RANTES). Endometriotic cells were implanted into the peritoneal cavity of mice, and these mice were injected estradiol benzoate (30 µg/kg) once each day for 14 days. The mice with endometriosis were then treated with 12, 25 or 50 mg/kg marrubiin. Reverse transcription-quantitative polymerase chain reaction was used to assess the mRNA expression of RANTES, and western blot analysis was used to analyze the protein expression of RANTES, TNF-α and PGE2. Inflammation factors were measured by ELISA. Treatment with marrubiin effectively improved lesion regression and inhibited toxicity in the mouse model of endometriosis. Marrubiin significantly inhibited endometrial lesions and monocyte chemotaxis in the mice with endometriosis, and reduced U937 cell migration. Calcium mobilization, levels of tumor necrosis factor-α and the secretion of RANTES were effectively suppressed by marrubiin treatment. The calcium levels were effectively induced, whereas the protein expression of prostaglandin E2 (PGE2) and formation of thromboxane B2 (TXB2) were effectively inhibited by marrubiin treatment. These findings indicated that the protective effect of marrubiin improved endometriosis in the mice through the suppression of inflammation and downregulation of the expression of RANTES, followed by mediation of the levels of calcium, PGE2 and TXB2.

Socheongryeong-tang (SCRT) is a herbal formula previously used to treat pulmonary diseases primarily caused by the common cold virus, including airway inflammation, asthma and allergy. The aim of the present study was to investigate the inhibitory effect of SCRT water extract and its 13 constituent components on chemokine and enzyme production in the human bronchial epithelium cell line BEAS-2B when induced by tumor necrosis factor-α and interleukin-4. The chemokines examined included regulated on activation of normal T-cell-expressed-and-secreted (RANTES), eotaxin and eotaxin-3. The SCRT water extract demonstrated a dose-dependent inhibition of RANTES, eotaxin, eotaxin-3 and matrix metalloproteinase-9 (MMP-9) in BEAS-2B cells. The 13 constituent compounds of SCRT water extract were quantitatively determined, and it was found that gallic acid, 6-gingerol and methyl eugenol produced the most potent inhibition of RANTES, eotaxin and eotaxin-3 as well as MMP-9 activity regardless of their concentration in SCRT water extract. Principal component analysis and hierarchical clustering analysis revealed that the inhibitory effect of these three compounds contributed to that of SCRT water extract. In conclusion, the results of the present study indicated that the inhibitory effects of SCRT on chemokine and enzyme production in BEAS-2B cells was associated with three of its constituent compounds, gallic acid, 6-gingerol and methyl eugenol. This therefore suggested the potential use of these compounds as anti-inflammatory agents.

Background: RANTES (regulated on activation, normal T cell expressed and secreted) expression is increased in inflammatory bowel disease (IBD). RANTES is produced at higher levels in granulomatous conditions, so increased RANTES expression can be expected in Crohn’s disease compared with ulcerative colitis. Aim: To compare RANTES expression between intestinal biopsy specimens of patients with Crohn’s disease and those with ulcerative colitis. Materials and methods: A prospective study of patients presenting with lower gastrointestinal symptoms at the Bahrain Specialist Hospital from July 2004 to April 2005 was carried out. Endoscopic colonic biopsy specimens were taken from every patient and subjected to (a) routine haematoxylin and eosin staining examination by light microscopy, (b) immunohistochemistry for examination of RANTES protein expression by light microscopy and (c) in situ hybridisation for examination of RANTES mRNA expression by light microscopy. RANTES expression was assessed and quantified. Results: 58 patients were enrolled to the study. Of them, 40 had IBD (21 had Crohn’s disease and 19 had ulcerative colitis), 15 were controls with normal colonic biopsy results or non-inflammatory lesions and 3 had colonic inflammatory lesions other than IBD. RANTES expression in lymphocytes or histiocytes was significantly higher (p = 0.04) in new patients with ulcerative colitis than in those with Crohn’s disease analysed by immunohistochemistry (IHC). Conclusion: RANTES expression in lymphocytes or histiocytes is significantly higher in patients with ulcerative colitis than in those with Crohn’s disease. Hence, RANTES IHC can be an effective method for distinguishing between biopsy specimens of patients with ulcerative colitis from those of patients with Crohn’s disease, where routine histological features are indeterminate. RANTES IHC may prove to be a useful technique for identifying early or equivocal granulomas.

Aim: To determine whether intravitreal injection of tacrolimus suppresses ongoing experimental autoimmune uveoretinitis (EAU) in rats. Methods: Rats were immunised with interphotoreceptor retinoid-binding protein peptide (R14) and given an intravitreal injection of tacrolimus on day 12 after immunisation. Intraocular inflammation was assessed by slit-lamp biomicroscopy and histopathological examination. Interferon γ and tumour necrosis factor α protein levels in the ocular tissues were measured. Gene expression of chemokines was determined in ocular tissues by reverse transcription-polymerase chain reaction. To evaluate the systemic effect of intravitreal injection of tacrolimus, delayed-type hypersensitivity was measured by ear swelling. Results: Clinical and pathological scores showed that ocular inflammation of tacrolimus-treated eyes was markedly less than that of vehicle-treated eyes. The amount of interferon γ and tumour necrosis factor α was considerably inhibited in tacrolimus-treated eyes. The gene expression of monocyte chemattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES) was markedly reduced in tacrolimus-treated eyes. Delayed-type hypersensitivity responses were not impaired in tacrolimus-treated rats. Conclusions: Intravitreal injection of tacrolimus was highly effective in suppressing the ongoing process of EAU without any side effects on systemic cellular immunity. This treatment may be useful in the management of patients with severe uveitis.