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Age-related inflammatory mediators in coronary artery disease (II)
... Overexpression of IL-34 is associated with autoimmune diseases, such as RA (36), inflammatory bowel disease (IBD) (37) and Sjogren's syndrome (38). Upregulated IL-34 is also detected in human atherosclerotic plaques, particularly correlating with unstable plaques (19), suggesting that the proinflammatory activities of IL-34 in the advanced stages of plaque development may contribute to acute coronary syndrome and premature death (39). In addition, a substantial circulating IL-34 level has been detected in CAD patients and is associated with the severity of comorbid CAD in heart failure (40,41) (Figure 2). ...
Atherosclerosis, which is a primary cause of cardiovascular disease (CVD) deaths around the world, is a chronic inflammatory disease that is characterised by the accumulation of lipid plaques in the arterial wall, triggering inflammation that is regulated by cytokines/chemokines that mediate innate and adaptive immunity. This review focuses on IL-32,-34 and-37 in the stable vs. unstable plaques from atherosclerotic patients. Dysregulation of the novel cytokines IL-32,-34 and-37 has been discovered in atherosclerotic plaques. IL-32 and-34 are pro-atherogenic and associated with an unstable plaque phenotype; whereas IL-37 is anti-atherogenic and maintains plaque stability. It is speculated that these cytokines may contribute to the explanation for the increased occurrence of atherosclerotic plaque rupture seen in patients with COVID-19 infection. Understanding the roles of these cytokines in atherogenesis may provide future therapeutic perspectives, both in the management of unstable plaque and acute coronary syndrome, and may contribute to our understanding of the COVID-19 cytokine storm.
... I have further collaborated with Cris and his PhD student with fruitful outcome (Chhabra et al. 2002). I have listed few selective publications over 31 years (Ramsay et al. 1994, Bao et al. 1996, Bao et al. 2000, Najib et al. 2012, Fang et al. 2013, Puranik et al. 2016, Liao et al. 2018, Fan et al. 2020a, initial achievement from Cris's group, and the following achievement by my own research group, but is benefit greatly from the great 3 years of PhD training under Prof dos Remedios. ...
As a non-English-speaking PhD student without previous scientific skills, I have been so lucky to be supervised and mentored by Professor Cristobal dos Remedios. In this commentary, I have commented my experience in dos Remedios laboratory. Finally, I would like to express my greatest appreciation to Professor dos Remedios for his kindness and mentorship over the last 31 years. His continuous support, which continues to the present, has been instrumental for the achievement of my current position.
... Endothelial expression of VCAM-1 and ICAM-1 was determined by quantitative immunohistochemistry using ImagePro Plus 4.5 software (Media Cybernetics, Silver Spring, MD) [20]. The results, which represent the average positive staining above the threshold, set by a blinded experienced pathologist, for individual arterial sections are expressed as image units. ...
Background:
The ability of Zn(II) and Cu(II) metal complexes of non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit acute arterial inflammation in vivo has been studied.
Results:
When acute vascular inflammation was induced in normocholesterolemic New Zealand White rabbits by inserting a non-occlusive silastic collar around the common carotid artery, a single oral dose of Cu(II)-indomethacin (Cu(II)Indo, 3 mg/kg) administered by laparotomy achieved a 67 % (8.2 ± 1.7 vs. 2.7 ± 0.4 image units, p < 0.05) reduction in endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) but did not inhibit endothelial intercellular adhesion molecule (ICAM-1) expression significantly. Treatment with Cu(II)-acemetacin (Cu(II)ACM, 3 mg/kg) led to a profound 88 % (8.2 ± 1.7 vs. 1.0 ± 0.5 image units, p < 0.01) reduction in endothelial VCAM-1 expression but did not inhibit ICAM-1 expression, while treatment with Zn(II)-acemetacin (Zn(II)ACM, 3 mg/kg) led to an 84 % (19.3 ± 1.0 vs. 3.1 ± 1.2 image units, p < 0.01) reduction in endothelial ICAM-1 expression and did not inhibit VCAM-1 expression. No adverse gastric, hepatic or renal effects were observed in treated animals.
Conclusion:
These findings provide the "proof of concept" that this novel class of drug, where there is complexation of NSAIDs with metal ions, has substantial anti-inflammatory effects in an animal model of acute vascular inflammation with the possibility of low rates of adverse effects.
... The cytokines IL-31, IL-32, IL-33 and IL-34 have recently been characterised with regard to various inflammatory conditions, with IL-31, -32 and -34 having proinflammatory effects whereas IL-33 has been shown to be potentially athero-protective both in vitro and in animal studies of experimental atherosclerosis [3][4][5][6]. Our recently published data described the distribution of these cytokines in post-mortem coronary samples [7]; however their expression in ex-vivo human carotid plaques, particularly their correlation with stable versus unstable plaque phenotypes and relationship with patient characteristics, has not yet been explored. ...
... For IL-10, IL-6, MMP-2, MMP-9 or F4/80 þ , the percentage of positive staining relative to the total area of interest was calculated. The cytokine/chemokine expression results were expressed as positive pixel per area of interest, i.e. image units, as previously described [23]. All data are expressed as mean AE standard error of the mean (SEM) and were analyzed using statistical software in GraphPad Prism Version 5.0 (GraphPad Software, CA, USA). ...
Saikosaponin-d (SSd) is an active extract from Radix Bupleuri, the dried root from the plant Bupleurum falcatum used in China for thousands of years to treat liver diseases. The SSd extract possesses valuable pharmacological activities including anti-cancer and anti-inflammatory effects; however, the mechanism underlying the anti-cancer activity of SSd is largely unknown. Here, we explored the mechanism of action of SSd as an anti-cancer agent for liver cancer in two human hepatocellular carcinoma cell lines. Using MTT and annexin-V-FITC/PI assays, Western blots, immunohistochemistry, qRT-PCR, luciferase reporter assay, and a JAK2-specific inhibitor (AG490), we demonstrated that the anti-tumorigenic effects of SSd act through the intermediatory p-STAT3/C/EBPβ signaling pathway to suppress cyclooxygenase (COX)-2. SSd effectively inhibited cell proliferation in a dose-dependent manner. Apoptosis was significantly increased in cells treated with SSd (2.5-15 µg/ml) with concurrent increase and decrease in pro- and anti-apoptosis proteins, respectively. COX-2, C/EBPβ, and p-STAT3 were significantly decreased, at both the translational and transcriptional levels, by SSd treatment. AG490 produced similar inhibitory effects on STAT3, p-STAT3, C/EBPβ, and COX-2. In conclusion, our data suggest that SSd controls liver cancer proliferation through suppression of the p-STAT3/C/EBPβ signaling pathway inhibiting COX2 expression. These findings further our understanding of the pharmacological action of SSd, providing new information on SSd mechanism of action and showing potential for SSd as a novel therapy for liver cancer.
Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1-like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE(-/-) mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33-treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNgamma in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG(1), but decreased IgG(2a), which is consistent with a Th1-to-Th2 switch. IL-33-treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE(-/-) mice compared with control IgG-treated mice. Furthermore, coadministration of an anti-IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.
Background: It has been suggested that Crohn's disease (CD) is associated with an exaggerated T-helper 1 cytokine response manifested by increased production of interleukin (IL)-12. IL-12 is a heterodimeric protein comprising 2 disulfide-linked subunits designated p35 and p40. Recently, IL-12-related cytokines, IL-23 and IL-27, were described. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 whereas its p19 subunit is distantly related to IL-12p35. IL-27 consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide.Aim: We sought to determine whether mucosal expression of IL-23p19 and IL-27p28 transcripts correlate with the inflammatory activity in inflammatory bowel disease (IBD).Patients/Methods: Messenger RNA expression in colonic mucosa from patients with Crohn's disease (CD; n = 37) and ulcerative colitis (UC; n = 19), and in non-IBD control subjects (specific colitis [SC]; n = 16) and normal, nondiseased control patients (n = 12) was measured by reverse-transcribed real-time polymerase chain reaction.Results: IL-23p19 was significantly increased in inflamed mucosa in CD (P = 0.0377) and to a lesser extent also in UC patients but not in SC patients. Elevation of IL-23p19 transcript levels in CD correlated with the severity of endoscopic lesions. IL-27p28 transcripts and EBI3 transcripts were significantly elevated only in active CD.Discussion: IL-23p19, IL-27p28, and EBI3 transcripts are strongly up-regulated in CD. The stimulatory effects of these cytokines on naive T cells in addition to a strongly synergistic action with IL-12 to trigger interferon-γ production may contribute to the perpetuation of the inflammatory process in patients with CD. Notably, increased expression of IL-23 and IL-27 transcripts in CD suggests a T helper 1-dominated immunologic function in this disease.
Dendritic cells (DCs) trigger adaptive immune responses and are an important source of antiviral cytokines. In hepatitis C virus (HCV) infection DC function is markedly impaired. Thus far, studies have focused on types I and II interferon (IFN). We studied IFN-lambda1 (IL-29) and IFN-lambda2/3 (IL-28A/B) serum levels in patients with different outcomes of HCV infection.
IFN-lambdas were measured by ELISAs detecting IL-29 or IL-28A and IL-28B, respectively. Results were stratified with respect to the recently discovered rs12979860 T/C polymorphism upstream of the IL-28B gene.
In general IL-29 serum levels exceeded IL-28A/B at least twofold, with IL-29 and IL-28A/B levels being significantly higher in carriers of the rs12979860 C allele than in TT homozygous individuals (p<0.02). IL-29 levels were substantially lower in patients with chronic hepatitis C than in healthy controls (p=0.005) and patients with spontaneously resolved hepatitis (p=0.001). Patients with acute hepatitis C showed IL-29 levels intermediate between chronic hepatitis C and normal controls; and IL-29 serum levels were higher in patients who spontaneously resolved hepatitis C than in those who became chronic. In vitro HCV proteins NS3 and E2 directly inhibited IL-29 production in poly I:C-stimulated purified DCs.
Our data suggest that HCV proteins modify IFN-lambda production in DCs. Carriers of the rs12979860 C allele associated with resolution of HCV infection exhibited increased IFN-lambda levels. Moreover, high IFN-lambda levels predisposed to spontaneous resolution of HCV infection. Thus, IFN-lambdas seem to play an important role in the control of hepatitis C.
Coronary heart disease, often associated with fatal outcomes, is increasingly common. Immune dysregulation is a key process in atherogenesis, yet age and other immune related factors are poorly characterised, especially in premature disease. The current study is to investigate the differential immunological mediators in the plaque specific to older and younger decedents.
Coronary artery plaques were collected from male decedents as follows: Younger (< 50 years; n=30), older (> 60 years; n=30) and control (n=10). Demographic and forensic pathological data were collected. Plaques were investigated, using detailed immunohistochemistry.
Older subjects had 20% elevated heart to body weight ratio compared to younger subjects (p<0.05), as well as 40% higher levels of plaque necrosis (p<0.05) and 90% more calcification (p<0.05). There was a three-fold higher amount of infiltrating CD3(+) T cells (p<0.05) and myeloperoxidase production (p<0.05) within plaque from older subjects than younger. Interestingly, older subjects had 50% and 70% lower numbers of infiltrating macrophage (p<0.05) and Foxp3(+) Treg cells (p<0.05), respectively, in the plaque compared to younger subjects. There were no significant age-dependent differences in IL-17 or IL-10 secretion.
Our data suggests that there are indeed age-dependent characteristics of culprit coronary plaque inflammation. In particular, older subjects demonstrate a plaque phenotype with higher amounts of inflammation and lower levels of Treg cells. Despite lower levels of inflammation, younger subjects also had fatal outcomes, indicating that alternative factors may be more important in plaque stability. These observations may have therapeutic consequences and hence warrant further investigation.
The immunological significance of IL-27 has been reported and discussed in various Th1/Th17-mediated inflammatory diseases. However, its importance in psoriasis is unknown. We investigated pathophysiological roles of IL-27 in psoriasis in this study. Serum IL-27 levels in psoriatic patients were significantly higher than those in healthy controls, and correlated with disease severity and serum IFN-gamma levels. An immunohistochemical analysis revealed the infiltration of IL-27-secreting cells in the papillary dermis of psoriatic skin lesions but not in skin lesions with atopic dermatitis or normal skin. Furthermore, IL-27 alone greatly induced in vitro CXCL9, CXCL10, and CXCL11 production and tyrosine phosphorylation of signal transducer and activator of transcription 1 in normal human keratinocytes, while it suppressed the tumor necrosis factor-alpha-induced production of IL-1alpha and CCL20. These results indicate that IL-27 may promote the onset of psoriasis, while it may simultaneously attenuate the expanded inflammation in this disease. Our results implicate potential therapeutic effects of IL-27 for psoriasis.
Although inflammation is a key process in atherogenesis, little is known about the inflammatory characteristics of culprit plaque in premature coronary artery disease (CAD). We investigated inflammation in coronary atheroma from subjects who died of premature CAD. From 2001-2005, we collected coronary plaque samples from consecutive cases of CAD (n=23) reported to the Department of Forensic Medicine which led to unexpected death in men aged <45 years. Coronary plaque from younger CAD decedents (<35 years, n=12) had lower levels of T cells (CD3+) (p=0.03), higher macrophage (CD 68+) (p=0.01) and T regulator cells (FOXP3+) (p=0.03) infiltration when compared to older CAD decedents (>35 years, n=11). Interestingly, there was no significant age-related difference between groups in the smooth muscle cell, apoA-I, myeloperoxidase and MMP-2 content within plaque. Hence, we demonstrate that higher expression of FOXP3 is associated with younger age at the time of fatal outcomes from CAD. These findings may have implications for plaque pathophysiology and thus warrant further investigation.
IL-31 is a cytokine expressed by T cells following activation with cytokines or staphylococcal exotoxins. A major function of IL-31 in atopic dermatitis (AD) is the induction of pruritus in the skin via the IL-31 receptor on sensory nerve cells. However, the regulation of the IL-31 receptor and pro-inflammatory functions of IL-31 in human monocytes and monocyte-derived cells are yet to be studied in detail.
To investigate the regulation and function of IL-31 receptors in resting and activated human monocytes, macrophages and dendritic cells.
Human monocytes, macrophages and dendritic cells were stimulated with staphylococcal exotoxins (SEB, alpha-toxin) or cytokines (IFN-gamma, IL-13). IL-31RA expression and regulation were then investigated at both the mRNA and the protein level. Subsequently, functional effects of IL-31 stimulation on cytokine secretion were measured at the protein level.
Staphylococcal exotoxins significantly up-regulated IL-31RA expression on monocytes and macrophages but not on dendritic cells at both the mRNA and the protein level. IL-31 enhanced the secretion of IL-1beta, IL-6 and IL-18 and up-regulated CD86 expression. In patients with AD, functional IL-31RA was also detected following stimulation of PBMC with IFN-gamma. However, this was not observed in healthy individuals.
IL-31 induces pro-inflammatory effects in activated human monocytes and macrophages. This may have implications for cutaneous inflammation in eczema where an over-expression of IL-31 has been described previously. Moreover, our findings provide a new link between staphylococcal colonization and the worsening of inflammation via IL-31. Further therapeutic considerations may include IL-31 as a target in AD.
It has been suggested that Crohn's disease (CD) is associated with an exaggerated T-helper 1 cytokine response manifested by increased production of interleukin (IL)-12. IL-12 is a heterodimeric protein comprising 2 disulfide-linked subunits designated p35 and p40. Recently, IL-12-related cytokines, IL-23 and IL-27, were described. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 whereas its p19 subunit is distantly related to IL-12p35. IL-27 consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide.
We sought to determine whether mucosal expression of IL-23p19 and IL-27p28 transcripts correlate with the inflammatory activity in inflammatory bowel disease (IBD).
Messenger RNA expression in colonic mucosa from patients with Crohn's disease (CD; n = 37) and ulcerative colitis (UC; n = 19), and in non-IBD control subjects (specific colitis [SC]; n = 16) and normal, nondiseased control patients (n = 12) was measured by reverse-transcribed real-time polymerase chain reaction.
IL-23p19 was significantly increased in inflamed mucosa in CD (P = 0.0377) and to a lesser extent also in UC patients but not in SC patients. Elevation of IL-23p19 transcript levels in CD correlated with the severity of endoscopic lesions. IL-27p28 transcripts and EBI3 transcripts were significantly elevated only in active CD.
IL-23p19, IL-27p28, and EBI3 transcripts are strongly up-regulated in CD. The stimulatory effects of these cytokines on naive T cells in addition to a strongly synergistic action with IL-12 to trigger interferon-gamma production may contribute to the perpetuation of the inflammatory process in patients with CD. Notably, increased expression of IL-23 and IL-27 transcripts in CD suggests a T helper 1-dominated immunologic function in this disease.
Sudden death is rare in young people, but it has a disproportionate impact on the community.
The purpose of this study was to determine the causes of sudden, natural death in persons aged 5-35 years.
All autopsies conducted at a forensic medicine facility in the years 1995-2004 (inclusive) were reviewed. This facility serves more than 2.5 million people in the eastern part of Sydney, Australia. Data collected included subject age, height, weight, gender, circumstances of death, and pathologic findings at autopsy. Deaths caused by trauma, accidental causes, drowning, and drug toxicity were excluded from analysis.
There were 427 nontraumatic, sudden deaths in the 10-year period (70.7% male). Cardiac causes accounted for 56.4%, noncardiac causes 39.3%, and undetermined cause 4.3%. The most common cardiac cause of sudden death was presumed arrhythmia in those with no or minimal structural heart disease (29.0%). Other cardiac causes were acute myocardial infarction (24.5%), myocarditis (11.6%), hypertrophic cardiomyopathy (5.8%), aortic dissection (5.4%), and dilated cardiomyopathy (5.4%). More than two thirds of deaths caused by acute myocardial infarction occurred in the age group from 30-35 years. Sudden cardiac death occurred during physical activity in 10.8% of cases. Sudden cardiac death was reported in a first-degree relative in 4.5% of decedents. The most common noncardiac causes of sudden death were epilepsy (23.8%), intracerebral hemorrhage (23.8%), asthma (16.1%), and pulmonary embolism (12.5%).
Presumed cardiac arrhythmia is the most common cause of sudden, natural death in the young. There was no reported history of sudden death among the relatives of most decedents.
IL-31 is produced by activated T lymphocytes, preferentially by TH2 cells. Transgenic mice overexpressing IL-31 have a phenotype resembling allergic dermatitis in human subjects.
We sought to evaluate the potential importance of IL-31 in the pathogenesis of human T cell-mediated skin diseases.
We analyzed total RNA taken from 149 skin biopsy specimens from patients with atopic dermatitis (AD), allergic contact dermatitis (ACD), or psoriasis in comparison with specimens taken from patients with healthy skin (n = 13) by using quantitative real-time PCR for the expression of TH1/TH2 cytokines.
We found statistically increased mRNA levels of IL-31 in biopsy specimens taken from patients with AD, irrespective of the severity of the disease and serum IgE levels. Moreover, IL-31 mRNA levels were strongly increased in many biopsy specimens taken from patients with ACD. However, no increased transcription of IL-31 could be detected in biopsy specimens taken from psoriatic plaques. A comparison of mRNA levels of IL-31 with TH1 or TH2 cytokines demonstrates a correlation of the expression of IL-31 with IL-4 and IL-13 but not with IFN-gamma. No significant increase of IL-31 receptor mRNA could be detected in any disease, whereas the second receptor subunit of IL-31, the oncostatin M receptor, seems to be enhanced transcribed in patients with psoriasis.
IL-31 expression is not only increased in patients with AD but also in those with ACD, 2 pruritic skin disorders. In both types of eczema, expression of IL-31 is associated with the expression of the TH2 cytokines IL-4 and IL-13.
IL-31 might contribute not only to the development of AD but also to ACD-provoked skin inflammation.
IL-32 is the name given to the NK4 transcript first reported in IL-2 activated T lymphocytes and natural killer cells 13 years ago without known function. The novel cytokine has six isoforms. In an study to isolate a soluble form of the IL-32 receptor from human urine, IL-32alpha bound proteinase-3 with high affinity and was not affected by enzyme inhibition. IL-32alpha/IL-32gamma were expressed as recombinant molecules. The cytokine exhibits properties characteristic of proinflammatory cytokines and also induces the degradation of inhibitory kappaB and phosphorylation of mitogen activated protein p38. Monoclonal antibodies to IL-32 identify its presence in a variety of human tissues from diseases states. Epithelial cells from healthy subjects express low levels of the cytokine, but in disease conditions such as chronic obstructive pulmonary disease, Crohn's disease and psoriasis, the expression increases markedly. IL-32 is a major transcript in gene array studies in epithelial cells stimulated with IFNgamma in vitro. In rheumatoid arthritis, synovial tissues reveals increased content of IL-32, which correlates with severity of disease. A highly significant correlation has been observed between the number of synovial and macrophagic cells positive for IL-32 and the level of erythrocytes sedimentation, IL-1beta, tumour necrosis factor alpha, and IL-18. Thus, IL-32 exhibits many properties of proinflammatory cytokines and associations with disease severity.