Levels of C-reactive protein, LDL, IL-1α, and IL-1β as Potential Indicators of Heart Disease

C-reactive protein, interleukin-1α, and interleukin-1β are biomarkers that are important in the early detection of heart disease and atherosclerosis. There are many different types of heart diseases, but coronary artery disease is the most common. Heart disease kills hundreds of thousands of people every year because it is usually detected late and its general complications at the later stages. Often, by the time a patient is diagnosed, the heart disease has progressed to its later stages where treatment is not as effective. One of the current diagnostic tests that are conducted is called an electrocardiogram (EKG), and it is very expensive, reducing cost-effectiveness. In this paper, the relevance of C-reactive protein, interleukin 1α, interleukin 1β, and low-density lipoprotein to the indication of heart diseases and the use of those in early detection is discussed. In addition, there is an in-depth review of the correlations between each of the biomarkers and the severity of atherosclerosis within patients.

PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.

Cyclic loading regime considered beneficial does not protect injured and interleukin-1-inflamed cartilage from post-traumatic osteoarthritis

Post-traumatic osteoarthritis is a degenerative musculoskeletal condition where homeostasis of articular cartilage is perturbated by lesions and inflammation, leading to abnormal tissue-level loading. These mechanisms have rarely been included simultaneously in in vitro osteoarthritis models. We modeled the early disease progression in bovine cartilage regulated by the coaction of (1) mechanical injury, (2) pro-inflammatory interleukin-1α challenge, and (3) cyclic loading mimicking walking and considered beneficial (15% strain, 1 Hz). Surprisingly, cyclic loading did not protect cartilage from accelerated glycosaminoglycan loss over 12 days of interleukin-1-culture despite promoting aggrecan biosynthesis. Our time-dependent data suggest that this loading regime could be beneficial in the first days following injury but later turn detrimental in interleukin-1-inflamed cartilage. Consequently, early anti-catabolic drug intervention may inhibit, whereas cyclic loading during chronic inflammation may promote osteoarthritis progression. Our data on the early stages of post-traumatic osteoarthritis could be utilized in the development of countermeasures for disease progression.

The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury

Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is released by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induced neutrophil infiltration and OL death throughout the spinal cord, mimicking what is seen at sites of SCI. These effects were abolished by co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which showed enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restored IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduced OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes is toxic for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS) and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, which induces astrocyte- and EC-mediated OL degeneration.

Association of Interleukin-1α Functional Polymorphism with Risk of Chronic Periodontitis in Han Chinese Population

Chronic periodontitis (CP) is a common inflammatory illness affecting a large proportion of humans. Genetic factors are thought to play important roles in its onset and development. A functional polymorphism (rs1800587) in the promoter of the interleukin-1α gene (−889 C/T) has been found to confer risk of CP primarily in Europeans, but the association between this variant and CP in the Chinese population remains less conclusive. In the current study, we aimed to investigate the association between rs1800587 and CP in case-control samples of Han Chinese origin. A total of 1,777 study subjects, including 884 CP patients and 893 healthy controls, were collected. Genotyping of rs1800587 was performed using the SNAPSHOT method, and statistical analyses were conducted to evaluate the association between rs1800587 and CP. In our sample, rs1800587 was significantly associated with the onset of CP (additive model, T-allele vs. C-allele, p = 0.00359, odds ratio = 1.446, 95% confidence intervals (CIs) = 1.127–1.855; dominant model, (TT + TC) vs. CC, p = 0.00250, odds ratio = 1.502, 95% CIs = 1.152–1.957; overdominant model, TC vs. (TT + CC), p = 0.00264, odds ratio = 1.508, 95% CIs = 1.152–1.976). The T-allele and [TC] genotypes of rs1800587 were significantly overrepresented in CP patients compared with controls. Our data suggest that rs1800587 of IL-1α is significantly associated with the risk of CP in Han Chinese subjects, further confirming its possible involvement in the disease.

Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis

Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies [A. M. Valdes, T. D. Spector, Nat. Rev. Rheumatol. 7, 23–32 (2011)]. We previously identified mechanosensitive PIEZO channels, PIEZO1 and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction in response to injury [W. Lee et al., Proc. Natl. Acad. Sci. U.S.A. 111, E5114–E5122 (2014); W. Lee, F. Guilak, W. Liedtke, Curr. Top. Membr. 79, 263–273 (2017)]. We therefore asked whether interleukin-1–mediated inflammatory signaling, as occurs in OA, influences Piezo gene expression and channel function, thus indicative of maladaptive reprogramming that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic cartilage tissue were studied. We found that interleukin-1α (IL-1α) up-regulated Piezo1 in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca2+ at baseline and in response to mechanical deformation. Elevated resting state Ca2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma. As intracellular substrates of this OA-related inflammatory pathomechanism, in porcine articular chondrocytes exposed to IL-1α, we discovered that enhanced Piezo1 expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1. CREBP1 directly bound to the proximal PIEZO1 gene promoter. Taken together, these signaling and genetic reprogramming events represent a detrimental Ca2+-driven feed-forward mechanism that can be rationally targeted to stem the progression of OA.