Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectiveness in vitro, in vivo and human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.

/pdf/interleukin-18-cytokine-in-immunity-inflammation-and-1amdu8gx.pdf

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

Objective This study aimed to investigate the association of plasma TNF-α, IL-6, and lL-10 levels and cytokine gene polymorphisms [TNF-α (-308 G→A), IL-6 (-174 C→G) and IL-10 (-1082 A→G, -819 T→C and -592 A→C)] in type 2 diabetes mellitus (T2DM) and obese patients. Subjects and methods One hundred and two T2DM patients and 62 controls were included in this study. Cytokine plasma levels were measured by the Cytometric Bead Array method. Genotyping was carried out by the polymerase chain reaction. Results IL-6 levels were significantly different between T2DM patients and controls. Interestingly, IL-6 levels were higher in T2DM patients with BMI > 30 kg/m2 compared with other patients and obese controls. The genotype and allele frequencies were similar between patients and controls. In the T2DM group, the SNP IL-10 -819 T/C showed a difference between the cytokine level and genotypes: IL-10 level in the TT genotype was significantly higher when compared to CC genotype. Conclusions These results suggest an association between IL-6 levels and obesity, and IL-10 levels and the SNP -819 T/C in T2DM. Knowledge of these variants in T2DM might contribute to a better understanding of the role of inflammation in the etiology and progression of this disease.

/pdf/il-6-tnf-a-and-il-10-levels-polymorphisms-and-their-4w0fd2gdzg.pdf

IL-6, TNF-α, and IL-10 levels/polymorphisms and their association with type 2 diabetes mellitus and obesity in Brazilian individuals

Autoimmune diseases are chronic immune diseases characterized by dysregulation of immune system, which ultimately results in a disruption in self-antigen tolerance. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) play essential roles in various autoimmune diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, multiple sclerosis (MS), etc. NLR proteins, consisting of a C-terminal leucine-rich repeat (LRR), a central nucleotide-binding domain, and an N-terminal effector domain, form a group of pattern recognition receptors (PRRs) that mediate the immune response by specifically recognizing cellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and triggering numerous signaling pathways, including RIP2 kinase, caspase-1, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and so on. Based on their N-terminal domain, NLRs are divided into five subfamilies: NLRA, NLRB, NLRC, NLRP, and NLRX1. In this review, we briefly describe the structures and signaling pathways of NLRs, summarize the recent progress on NLR signaling in the occurrence and development of autoimmune diseases, as well as highlight numerous natural products and synthetic compounds targeting NLRs for the treatment of autoimmune diseases.

NOD-like receptors in autoimmune diseases.

Urinary markers of nucleic acid oxidation may be useful biomarkers in diabetes. It has been demonstrated that T2DM patients have an increased level of oxidative DNA damage; however, it is unclear whether increased DNA damage may be related to a greater degree of inflammation and insulin resistance. Thus, the aim of this present study was to investigate the relation of the impact of oxidative DNA damage, assessed by urinary 8-OHdG, on the levels of inflammatory cytokines, as well as insulin resistance. In addition, we also investigated the diagnostic ability of urinary 8-OHdG in the identification of microvascular complications in T2DM.A case-control study, enrolling 22 healthy controls and 54 subjects with T2DM, was performed to evaluate the relation between oxidative DNA damage and interleukin-6 (IL-6), IL-1,tumor necrosis factor-alpha (TNF-α), IL-10, and Homeostasis Model Assessment (HOMA-IR) index. T2DM patients presented higher urinary 8-OHdG, IL-6, IL-1, TNF-α levels and HOMA-IR, and lower IL-10 levels than control subjects. Moreover, urinary 8-OHdG levels were significantly higher in the group T2DM with microvascular complications when compared to the without complications. The areas under the curve for urinary 8-OHdG and urinary albumin were, respectively, 0.836 (P<0.001) and 0.786 (P=0.002). Thus, urinary 8-OHdG has a slightly higher ability to discriminate microvascular complications in T2DM compared with urinary albumin. It was also demonstrated that T2DM patients with higher median of urinary 8-OHdG had significantly elevated levels of IL-6, TNF-α and HOMA-IR, and decreased IL-10 levels. Our findings showed that T2DM patients with higher urinary 8-OHdG levels showed a greater inflammatory degree and higher insulin resistance. It is possible to speculate that T2DM patients present a cascade of events as increasing metabolic abnormalities such as insulin resistance and inflammatory activation, as well as increased ROS generation factors that may contribute directly to greater oxidative DNA damage.

Oxidative DNA damage is associated with inflammatory response, insulin resistance and microvascular complications in type 2 diabetes.

Cell death is an essential immunological apparatus of host defense, but dysregulation of mutually inclusive cell deaths poses severe threats during microbial and parasitic infections leading to deleterious consequences in the pathological progression of infectious diseases. Nucleotide-binding oligomerization domain (NOD)-Leucine-rich repeats (LRR)-containing receptors (NLRs), also called nucleotide-binding oligomerization (NOD)-like receptors (NLRs), are major cytosolic pattern recognition receptors (PRRs), their involvement in the orchestration of innate immunity and host defense against bacteria, viruses, fungi and parasites, often results in the cleavage of gasdermin and the release of IL-1β and IL-18, should be tightly regulated. NLRs are functionally diverse and tissue-specific PRRs expressed by both immune and non-immune cells. Beyond the inflammasome activation, NLRs are also involved in NF-κB and MAPK activation signaling, the regulation of type I IFN (IFN-I) production and the inflammatory cell death during microbial infections. Recent advancements of NLRs biology revealed its possible interplay with pyroptotic cell death and inflammatory mediators, such as caspase 1, caspase 11, IFN-I and GSDMD. This review provides the most updated information that caspase 8 skews the NLRP3 inflammasome activation in PANoptosis during pathogen infection. We also update multidimensional roles of NLRP12 in regulating innate immunity in a content-dependent manner: novel interference of NLRP12 on TLRs and NOD derived-signaling cascade, and the recently unveiled regulatory property of NLRP12 in production of type I IFN. Future prospects of exploring NLRs in controlling cell death during parasitic and microbial infection were highlighted.

Nod-like Receptors: Critical Intracellular Sensors for Host Protection and Cell Death in Microbial and Parasitic Infections

Association of the interleukin-10 -592A/C, -1082G/A and -819T/C gene polymorphisms with type 2 diabetes: a meta-analysis.

Tumour suppressor protein 53 (p53) plays a central role in apoptosis, cell proliferation and death. Previously studies found contribution of functional p53 Arg72Pro polymorphism (TP53 rs1042522G/C polymorphism) in the development of systemic lupus erythematosus (SLE) remains controversial. In this study, for the first time, we evaluated its association with SLE in a Chinese Han population. This case–control study enrolled 1470 SLE patients and 2283 healthy controls. The genotyping of TP53 rs1042522 polymorphism was determined by Sequenom Mass ARRAY technology. Statistical analysis was conducted by Chi-square test (χ
 2 test). Odds ratio (OR) with 95% confidence interval (CI) was calculated using unconditional logistic regression with adjusting age and sex. Allele and genotype frequencies of TP53 rs1042522G/C polymorphism showed statistically significant difference between the SLE patients and the normal controls (C vs. G: OR = 0.89, 95% CI 0.89–0.97, p = 0.01; (GC + CC) vs. GG using recessive model: OR = 0.84, 95% CI 0.73–0.96, p = 0.01; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74–0.99, p = 0.04; CC vs. GG using co-dominant model: OR = 0.80, 95% CI 0.66–0.96, p = 0.02; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74–0.99, p = 0.02). In addition, there was weak association between discoid rash and distribution of TP53 rs1042522G/C polymorphism in SLE patients (C vs. G: OR = 1.25, 95% CI 1.00–1.55, p = 0.04; CC vs. GG using co-dominant model: OR = 1.54, 95% CI 1.10–2.36, p = 0.04). Our finding suggests a significant relationship between the TP53 rs1042522G/C polymorphism and SLE. TP53 rs1042522G/C polymorphism would be promising as an indicator of SLE as well as the therapeutic target if its functions and mechanisms could be further investigated.

Association study between the TP53 Rs1042522G/C polymorphism and susceptibility to systemic lupus erythematosus in a Chinese Han population.

Nucleotide-binding oligomerization domain 2 (NOD2) is one of the most prominent member of the NOD-like receptors protein family that functions as intracellular pattern recognition receptors. Numerous studies have suggested the importance of NOD2 in defensing against microbial infections, regulation of the inflammatory process. It is shown that NOD2 contributes to the pathogenesis of various autoimmune and chronic inflammatory diseases, such as Crohn’s disease, rheumatoid arthritis. The aim of this study is to summarize our current understandings of NOD2 function and the role of NOD2 in systemic lupus erythematosus (SLE). The following databases were searched: Pubmed, EMBASE and Web of Science for English-language sources, using the terms “lupus,” “systemic lupus erythematosus,” ‘‘SLE,” “immunity,” “inflammatory” and “NOD2.” Emerging data evidences that NOD2 has important biological effects in autoimmunity and inflammatory and might take part in the pathogenesis of SLE. Studies exploring the relationship between NOD2 and SLE are very limited. Whether NOD2 could be a potentially valuable therapeutic target for treatment for SLE, more understanding of the mechanism of NOD2 is needed in the future in SLE.

Potential roles of nucleotide-binding oligomerization domain 2 in the pathogenesis of systemic lupus erythematosus

Published data on the association between interleukin (IL)-18 gene polymorphisms (−137 C/G, −607 A/C) and type 1 diabetes (T1D) risk are inconclusive. To obtain a more precise estimation of the association between the IL-18 gene polymorphisms and T1D, a meta-analysis was performed. A total of 11 studies including 5,945 cases and 6,404 controls were included in the analysis of the association between −137 C/G and T1D risk. No significant association between −137 C/G and T1D risk was observed in the total population [C vs. G: odds ratio (OR)=1.02, 95% confidence interval (CI)=0.87–1.20; CC + CG vs. GG: OR=1.05, 95% CI=0.87–1.25; CC vs. CG + GG: OR=0.96, 95% CI=0.68–1.36]. No significant association was identified in the stratified analysis for all the genetic models in the European population. Concerning −607 A/C, 10 studies involving 3,048 patients and 3,377 controls were included in this meta-analysis. When all the studies were pooled, the results showed no evidence for a significant association between IL-18 −607 A/C polymorphism and T1D risk (A vs. C: OR=0.93, 95% CI=0.81–1.06; AA + AC vs. CC: OR=0.99, 95% CI=0.89–1.10; AA vs. AC + CC: OR=0.81, 95% CI=0.60–1.09). In addition, similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests a lack of association between the two polymorphisms (−137 C/G, −607 A/C) in the IL-18 gene and T1D. Due to the limitation of the number of the studies, the conclusions drawn should be considered with caution. Larger scale primary studies are required to evaluate the association between IL-18 gene polymorphisms and T1D.

/pdf/association-of-the-interleukin-18-137-c-g-607-a-c-42qu1xbk2q.pdf

Association of the interleukin-18 -137 C/G, -607 A/C polymorphisms with type 1 diabetes: A meta-analysis.

Background: The aim of this study was to evaluate the efficacy of acupuncture for treating rheumatoid arthritis (RA).
Materials and Methods: The literature were searched using 6 databases, including Pubmed, Embase, Chinese Biomedical
Literature Database, China National Knowledge Infrastructure, VIP and Wanfang database up to December 2013, without language
restrictions. All randomized clinical trials (RCTs) comparing acupuncture treatment with non-acupuncture treatment of RA was
considered. Methodological quality was assessed using the Jadad score.
Results: After strict screening, a total of 21 studies containing 1772 participants were included. The meta-analysis indicated that a
significant benefit of acupuncture compared with non-acupuncture on improving the symptoms of RA (pooled RR = 1.19, 95% CI
1.08–1.31, Z = 3.47, P = 0.001). In the subgroup analysis, 9 RCTs showed significant effects of acupuncture for response rate
compared with western medicine (RR = 1.26, 95% CI 1.02–1.55, Z = 2.19, P = 0.028); 5 RCTs showed significant effects of
acupuncture plus traditional Chinese drug compared with traditional Chinese drug (RR = 1.17, 95% CI 1.07–1.29, Z = 3.31, P =
0.001); 5 RCTs showed beneficial effects of acupuncture plus western medicine compared with western medicine (RR = 1.27, 95%
CI 1.06–1.53, Z = 2.56 P = 0.01).
Conclusion: This meta-analysis demonstrates that acupuncture may have a favorable effect on treating RA. However, the evidence
was limited by the small sample size and the low methodological quality. Considering the potential of acupuncture, more researches
and well-designed, rigorous and large clinical trials are needed.

/pdf/effects-of-acupuncture-on-rheumatoid-arthritis-a-systematic-1bfeatzohm.pdf

Effects of acupuncture on rheumatoid arthritis: a systematic review and meta-analysis

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