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The purpose of the present study was to investigate the effect of intra-articular injections of autologous conditioned serum on human hip osteoarthritis and to test whether a potential treatment effect might be increased by additional injections of steroids and the recombinant interleukin-1 receptor antagonist protein anakinra. We compared the effects of autologous conditioned serum 46 hip osteoarthritis patients), autologous conditioned serum+cortisone (56 patients), and autologous conditioned serum+cortisone+recombinant interleukin-1 receptor antagonist protein (17 patients) in a retrospective clinical study by means of the Visual Analogue Scale for pain (pre- vs posttreatment). Over 14 months, treatment resulted in a large, statistically significant improvement for patients in all three groups, independent of the severity of osteoarthritis. Neither cortisone nor cortisone+recombinant interleukin-1 receptor antagonist protein increased the beneficial treatment effect over and above the effect of autologous conditioned serum alone. Autologous conditioned serum successfully reduces pain in hip osteoarthritis. In severe hip osteoarthritis, the sole application of autologous conditioned serum can be even more beneficial than the combination of autologous conditioned serum with steroids.

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.

Purpose A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. Methods Patients’ and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1β were analyzed for single or multiple marker ( n  = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. Results Inflammation in IVIG-resistant KD ( n  = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS ( n  = 13) and MIS-C ( n  = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1β signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1β resulted in concentration-dependent LRG1 release. Conclusion Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1β signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.

Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.

Osteoarthritis (OA), which is the most common degenerative joint disorder, has been considered a non-inflammatory disease with abnormal mechanics. Interleukin (IL)-17 is a pleiotropic cytokine involved in inflammatory diseases and their production is driven by the cytokine including IL-1 and IL-23. However, little is known about the mechanism of IL-17 in the development of OA. Here, we investigated the role of IL-17 in the pathogenesis of OA using monosodium iodoacetate (MIA)-injected IL-17 and IL-1 receptor antagonist (IL-1Ra) double-deficient mice. In MIA-injected IL-1Ra KO mice, nociceptive properties, degree of cartilage damage, and the level of inflammatory factors in articular cartilage were increased compared to MIA-injected wild-type mice. Interestingly, the intestinal architecture was impaired in IL-1Ra KO mice compared to wild-type mice and the damage was further exacerbated by MIA injection. Deficiency of IL-17 reduced nociceptive properties and cartilage destruction, as well as inflammation-related factors in MIA-injected IL-1Ra KO mice compared to MIA-injected wild-type mice. Furthermore, IL-17-treated chondrocytes from OA patients showed enhanced expression of catabolic factors that are involved in the destruction of cartilage in OA. IL-17 accelerates the destruction of cartilage and small intestine via regulation of several inflammatory mediators in an OA murine model. These results suggest that IL-17 plays a critical role in the development of OA.

Background The acute phase response (APR) to CNS insults contributes to the overall magnitude and nature of the systemic inflammatory response. Aspects of this response are thought to drive secondary inflammatory pathology at the lesion site, and suppression of the APR can therefore afford some neuroprotection. In this study, we examined the APR in a mouse model of traumatic spinal cord injury (SCI), along with its relationship to neutrophil recruitment during the immediate aftermath of the insult. We specifically investigated the effect of IL-1 receptor antagonist (IL-1RA) administration on the APR and leukocyte recruitment to the injured spinal cord. Methods Adult female C57BL/6 mice underwent either a 70kD contusive SCI, or sham surgery, and tissue was collected at 2, 6, 12, and 24 hours post-operation. For IL-1RA experiments, SCI mice received two intraperitoneal injections of human IL-1RA (100mg/kg), or saline as control, immediately following, and 5 hours after impact, and animals were sacrificed 6 hours later. Blood, spleen, liver and spinal cord were collected to study markers of central and peripheral inflammation by flow cytometry, immunohistochemistry and qPCR. Results were analysed by two-way ANOVA or student’s t-test, as appropriate. Results SCI induced a robust APR, hallmarked by elevated hepatic expression of pro-inflammatory marker genes and a significantly increased neutrophil presence in the blood, liver and spleen of these animals, as early as 2 hours after injury. This peripheral response preceded significant neutrophil infiltration of the spinal cord, which peaked 24 hours post-SCI. Although expression of IL-1RA was also induced in the liver following SCI, its response was delayed compared to IL-1β. Exogenous administration of IL-1RA during this putative therapeutic window was able to suppress the hepatic APR, as evidenced by a reduction in CXCL1 and SAA-2 expression as well as a significant decrease in neutrophil infiltration in both the liver and the injured spinal cord itself. Conclusions Our data indicate that peripheral administration of IL-1RA can attenuate the APR which in turn reduces immune cell infiltration at the spinal cord lesion site. We propose IL-1RA treatment as a viable therapeutic strategy to minimise the harmful effects of SCI-induced inflammation.

Hyperinflammation is the hallmark of Kaposi’s sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone, which functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of the NF-κB pathway and IL-1α expression. These results reveal an important role of the IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies. Kaposi’s sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce IL-1Ra. This work has identified IL-1-mediated inflammation as a potential therapeutic target and dexamethasone as a potential therapeutic agent for KSHV-induced malignancies.

To compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes. Acute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed. Enhanced phagocytic activation of gout monocytes under basal conditions ( ) was associated with ROS generation and MSU stimulated IL-1β secretion ( ). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion ( ). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes ( ). PP2A inhibition reversed rhPRG4's effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice ( ) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx ( ). MSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and , PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.

Wound healing requires a delicate balance between cellular and molecular factors, all affected by reactive oxygen species (ROS). While ROS decontaminate, they also might lead to impaired wound healing, as evident in radiation-exposed skin and in venous insufficiency. Human alpha-1 antitrypsin (hAAT) is a circulating antiprotease that is anti-inflammatory and tissue-protective. Accordingly, tissue repair is enhanced in hAAT-rich conditions. hAAT undergoes oxidative modification in high-ROS environments, which alters its functional properties. While its antiprotease function is lost, the consequences of oxidation on its anti-inflammatory and tissue-protective properties are still under investigation. To explore this, excisional skin wound closure rates were first examined on irradiated skin and then tested using an iron-loading venous insufficiency model. The former was tested on hAAT transgenic mice, the latter on wild-type mice using topical clinical-grade hAAT. In-vitro, hAAT was oxidized using H 2 O 2 (0.5, 5 and 25 mM), then tested for elastase inhibition and added to an in-vitro A549 epithelial cell gap closure assay and a RAW 264.7 macrophage cell response assay. ROS levels, inflammatory responses and NRF2/ARE activation were determined. Results demonstrated wound closure was impaired in wild-type mice by both radiation and iron. In contrast, hAAT-transgenic mice exhibited accelerated wound closure in both normal and irradiated skin, and topical hAAT improved wound healing in the venous insufficiency model. hAAT OX lacked elastase inhibition across the three oxidation levels, yet highly oxidized hAAT (hAAT OX 25mM ) impaired epithelial gap closure and weakly oxidized hAAT (hAAT OX 0.5mM ) enhanced gap closure. All forms of hAAT OX elevated ROS in macrophages, as well as the expression of iNOS and catalase, IL-1β, TNFα and CXCL-1. Unexpectedly, the NRF2/ARE pathway was activated by hAAT OX 25mM and suppressed by hAAT OX 0.5mM , and hAAT OX 0.5 mM induced IL-1 receptor antagonist expression. In conclusion, oxidation levels of hAAT modify its effects on inflammation and tissue repair. While protease inhibition is lost, anti-inflammatory and repair attributes are maintained under low oxidative conditions, suggesting a molecular profile that is physiologically attuned to local signals. Considering its safety record, the study proposes that hAAT therapy is poised for trials in the context of defective tissue repair under oxidative conditions.

Objective The objective of this study was to investigate whether interleukin-1 (IL-1) gene polymorphisms are associated with susceptibility to Behçet’s disease (BD) and clinical manifestations of the disease. Methods In this cross-sectional study, we enrolled 110 patients with BD and age-and gender-matched 120 healthy controls. Five polymorphic regions of the IL-1 gene including rs 1800587 (IL1A-889 C/T), rs 2234650 (IL1R1), rs 16944 (IL1B-511 C/T), rs 315952 (IL1RN), and rs1143634 (IL1B-3954 C/T) were analyzed by using the real-time polymerase chain reaction system. Allele frequencies and genotypes were compared between groups. p ≤ 0.05 was accepted as statistically significant. Results The mean age of the patients with BD was 41 ± 12.4 years. The two groups were similar in terms of the age and gender distribution. The vast majority of BD patients had mucocutaneous involvement. The mean disease duration was 83.7 ± 67.8 months among the patients. The frequencies of each polymorphism in the IL-1 gene were similar between patients with BD and healthy controls. Conclusion The frequencies of variable IL-1 gene polymorphisms were similar between patients with BD and healthy controls.