PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response.

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared with healthy controls. Plasma levels of IL-1ß, IL-1RA, and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1, as well as of PD1 promoter methylation and PD1-targeting miR-15-5p, in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.

Molecular basis of the therapeutic properties of hemorphins.

Hemorphins are endogenous peptides, 4-10 amino acids long, belonging to the family of atypical opioid peptides released during the sequential cleavage of hemoglobin protein. Hemorphins have been shown to exhibit diverse therapeutic effects in both human and animal models. However, the precise cellular and molecular mechanisms involved in such effects remain elusive. In this review, we summarize and propose potential mechanisms based on studies that investigated the biological activity of hemorphins of different lengths on multiple therapeutic targets. Special emphasis is given to molecular events related to renin-angiotensin system (RAS), opioid receptors and insulin-regulated aminopeptidase receptor (IRAP). This review provides a comprehensive coverage of the molecular mechanisms that underpin the therapeutic potential of hemorphins. Furthermore, it highlights the role of various hemorphin residues in pathological conditions, which could be explored further for therapeutic purposes.

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

Long-term Effect of Injection Treatment for Osteoarthritis in the Knee by Orthokin Autologous Conditioned Serum.

Background Orthokin is an intra-articular autologous conditioned serum (ACS). Its use might have a beneficial biological effect on pain and function of osteoarthritis in the knee. However, earlier studies lack any consensus on its clinical application and disease modifying effect. Objective The aim of this study was to investigate the long-term effect of Orthokin injection treatment on prevention of surgical treatment for end-stage knee osteoarthritis. Study Design Prospective cohort study. Methods Patients of the previously published Orthokin cohort were contacted to determine whether any intra-articular surgical intervention or osteotomy of the study knee had taken place during the past decade. A log-rank test was performed to evaluate the differences in the survival distribution for the 2 types of intervention: Orthokin versus placebo. Results The survival distributions for the 2 interventions were not statistically significantly different, χ2(1) = 2.069, P = 0.150. After 7.5 ± 3.9 years, 46.3% of the placebo and 40.3% of the Orthokin group had been treated surgically. Conclusion The use of Orthokin in knee osteoarthritis patients did not result in a delay regarding surgical treatment. Clinical Relevance The intra-articular use of Orthokin does not seem to prevent or delay surgical intervention at 10 years after treatment for end-stage knee osteoarthritis.

Mechanisms of epithelial thickening due to IL-1 signalling blockade and TNF-α administration differ during wound repair and regeneration.

IL-1 and TNF-α are always present during wound repair, but their pleiotropic and synergistic effects are incompletely understood. In this work, we evaluated the role of IL-1 in wound repair, and examined whether TNF-α administration impaired scarless wound repair. First, we characterised wound repair in outbred CD-1 mice according to age and sex in an ear punch wound model. Then, we examined the effects of Interleukin 1 receptor antagonist (IL-1ra) and TNF-α placement inside ear wounds by means of loaded Heparin beads in young and middle-aged male and female mice. Wounds in middle-aged females repaired with scarless characteristics, whereas those in young males showed fibrotic scarring. Rather than improving wound repair in young males, IL-1 signalling blockade increased epithelial thickness and IL-1ß and TNF-α expression, and diminished epidermal apoptosis. TNF-α impaired wound repair in middle-aged females, which exhibited acanthosis and overexpression of IL-1, but no change in apoptosis. These findings suggest that this mechanism of epidermal thickening differs from that observed in IL1-ra-treated animals.

Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra.

OBJECTIVES: The study of the proinflammatory role of uric acid has focused on the effects of its crystals of monosodium urate (MSU). However, little is known whether uric acid itself can directly have proinflammatory effects. In this study, we investigate the priming effects of uric acid exposure on the cytokine production of primary human cells upon stimulation with gout-related stimuli. METHODS: Peripheral blood mononuclear cells (PBMCs) were harvested from patients with gout and healthy volunteers. Cells were pretreated with or without uric acid in soluble form for 24 h and then stimulated for 24 h with toll-like receptor (TLR)2 or TLR4 ligands in the presence or absence of MSU crystals. Cytokine production was measured by ELISA; mRNA levels were assessed using qPCR. RESULTS: The production of interleukin (IL)-1ß and IL-6 was higher in patients compared with controls and this correlated with serum urate levels. Proinflammatory cytokine production was significantly potentiated when cells from healthy subjects were pretreated with uric acid. Surprisingly, this was associated with a significant downregulation of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra). This effect was specific to stimulation by uric acid and was exerted at the level of gene transcription. Epigenetic reprogramming at the level of histone methylation by uric acid was involved in this effect. CONCLUSIONS: In this study we demonstrate a mechanism through which high concentrations of uric acid (up to 50 mg/dL) influence inflammatory responses by facilitating IL-1ß production in PBMCs. We show that a mechanism for the amplification of IL-1ß consists in the downregulation of IL-1Ra and that this effect could be exerted via epigenetic mechanisms such as histone methylation. Hyperuricaemia causes a shift in the IL-1ß/IL-1Ra balance produced by PBMCs after exposure to MSU crystals and TLR-mediated stimuli, and this phenomenon is likely to reinforce the enhanced state of chronic inflammation.

High-density lipoproteins inhibit urate crystal-induced inflammation in mice.

OBJECTIVES: To investigate the effects and mechanisms of action of high-density lipoproteins (HDL) in monosodium urate (MSU) crystal-induced inflammation -that is, gouty inflammation, in vivo. METHODS: Air pouches raised on the backs of mice were injected with MSU crystals or tumour necrosis factor (TNF) in the presence or absence of HDL and/or interleukin (IL)-1 receptor antagonist (IL-1Ra) for 3 h. Leucocyte count and neutrophil percentage in pouch fluids were measured using a haemocytometer and May-Grünwald-Giemsa staining. The cytokine production and expression in the pouch were measured by ELISA and quantitative RT-PCR. RESULTS: MSU crystals induced leucocyte infiltration, mostly neutrophils, and the release of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C-C motif) ligand 2 (CCL2) and IL-1Ra in pouch fluids. TNF remained under the detection limit. MSU crystals triggered IL-1ß, IL-6 and CXCL1 expression in both pouch exudates and membranes, whereas CCL2 and TNF mRNA were not modulated. The co-injection of MSU crystals and HDL inhibited leucocyte influx by 59% and neutrophil infiltration by 83% and, in turn, both protein and mRNA levels of all assessed proinflammatory cytokines were reduced, but not those of IL-1Ra. Similar results were obtained when mice were injected with MSU crystals pretreated with HDL or TNF instead of crystals. When HDL and IL-1Ra were added together they displayed additional inhibition, suggesting different mechanisms of action. CONCLUSIONS: This study demonstrated that HDL may represent an important factor in the modulation of gouty inflammation by acting on both tissue and infiltrating cells -that is, synovial tissue and synovial fluid cells. HDL display anti-inflammatory activity, in part, by interacting with crystals but also by directly acting on cells.

Matrilin-3 induction of IL-1 receptor antagonist is required for up-regulating collagen II and aggrecan and down-regulating ADAMTS-5 gene expression.

INTRODUCTION: Deletion or mutation of the gene encoding the cartilage extracellular matrix (ECM) protein matrilin-3 (MATN3) results in the early onset of osteoarthritis (OA), suggesting chondroprotective properties of MATN3. To understand the mechanisms underlying these properties, we determined the effects of MATN3 protein on the expression of several key anabolic and catabolic genes involved in chondrocyte homeostasis, and the dependence of such regulation on the anti-inflammatory cytokine: IL-1 receptor antagonist (IL-1Ra). METHODS: The effects of recombinant human (rh) MATN3 protein were examined in C28/I2 immortalized human chondrocytes, primary human chondrocytes (PHCs), and primary mouse chondrocytes (PMCs). Messenger RNA levels of IL-1Ra, COL2A1, ACAN, MMP-13, and ADAMTS-4 and -5 were determined using real-time RT-PCR. Knocking down IL-1Ra was achieved by siRNA gene silencing. IL-1Ra protein levels were quantified by ELISA and the Bio-Plex Suspension Array System. COL2A1 protein level was quantified using Western blot analysis. Statistic analysis was done using the two-tailed t-test or one-way ANOVA. RESULTS: rhMATN3 protein induced gene expression of IL-1Ra in C28/I2 cells, PHCs, and PMCs in a dose- and time-dependent manner. Treatment of C28/I2 cells and PHCs with MATN3 protein stimulated gene expression of COL2A1 and ACAN. Conversely, mRNA levels of COL2A1 and ACAN were decreased in MATN3 KO mice. MATN3 protein treatment inhibited IL-1ß-induced MMP-13, ADAMTS-4 and ADAMTS-5 in C28/I2 cells and PHCs. Knocking down IL-1Ra abolished the MATN3-mediated stimulation of COL2A1 and ACAN and inhibition of ADAMTS-5, but had no effect on MATN3 inhibition of MMP-13 mRNA. CONCLUSION: Our findings point to a novel regulatory role of MATN3 in cartilage homeostasis due to its capacity to induce IL-1Ra, to upregulate gene expression of the major cartilage matrix components, and to downregulate the expression of OA-associated matrix-degrading proteinases in chondrocytes. The chondroprotective properties of endogenous MATN3 depend partly on its induction of IL-1Ra. Our findings raise a possibility to use rhMATN3 protein for anti-inflammatory and chondroprotective therapy.

Baseline sebum IL-1α is higher than expected in afro-textured hair: a risk factor for hair loss?

OBJECTIVE: To investigate changes in sebum cytokines in response to hair cosmetics. Design and setting A prospective study at a University hospital. METHODS: We used a novel method for scalp surface sebum collection (Sebutape(®)) on three visits, sequentially a week apart, to investigate changes in six cytokines in 36 healthy women before and after shampoo and compared various chemical treatments (ammonium thioglycolate, "lye" sodium hydroxide and "no-lye" guanidine hydroxide relaxers) performed by a professional hairdresser. RESULTS: Significant levels detected were IL-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1ra), which were higher in untreated scalp vs. forehead: P < 0.001. Baseline levels of scalp sebum IL-1α were 18 times higher than IL-1ra. The levels of IL-1α decreased uniformly after shampoo (visit 1) and various chemical treatments (both crown and vertex all P < 0.001 - visit 2) but increased on follow-up at visit 3. Decreases in IL-1ra mimicked IL-1α at the vertex [after shampoo (P = 0.018) and visit 3 (P = 0.014)], but not on the crown, a finding which may suggest site-specific scalp predisposition to inflammation. The ratio of IL-1ra/IL-1α increased in all groups after all chemical treatments and on follow-up (all P < 0.001) but was surprisingly not significantly different from natural hair that underwent shampoo. LIMITATIONS: A wider cytokine panel may reveal response differences in treatment groups. CONCLUSIONS: Baseline inflammatory scalp cytokines are higher than expected and reduce with shampooing. Scrutiny of the influence of hair moisturizer formulations and shampoo intervals and studies investigating pro-fibrotic cytokines are required. This may elucidate the predilection of afro-textured hair to scarring alopecia.

Glatiramer acetate (GA), the immunomodulatory drug, inhibits inflammatory mediators and collagen degradation in osteoarthritis (OA) cartilage.

OBJECTIVE: Glatiramer acetate (GA), the generic name for Copaxone, an immunomodulatory agent, has been shown to induce interleukin-1 receptor antagonist (IL-1Ra) production in macrophages. We therefore tested the effects of GA on the catabolic activities of osteoarthritis (OA) chondrocytes. DESIGN: Primary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E(2) (PGE(2)) were estimated in the cell culture supernatants and in vitro MMP-13 activity was measured using fluorogenic substrate. TaqMan Real-Time quantitative polymerase chain reaction (RT-qPCR) was performed to estimate relative expression levels of genes. RESULTS: GA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100 µg) inhibited: (1) spontaneous collagen degradation as assayed by CTX II enzyme-linked immunosorbent assay (ELISA) [mean CTX II (ng/g cartilage)] in control was 7.79 [95% confidence interval (CI) 2.57-13.02]-3.415 (95% CI 0.81-6.02) (P=0.0286); (2) spontaneous proMMP-13 secretion [mean MMP-13 (ng/g cartilage)] in control was 16.98 (95% CI 7.739-26.23)-6.973 (95% CI 1.632-12.31) (P=0.0286); (3) production of IL-1ß-induced inflammatory mediators such as nitric oxide (NO) [mean NO (µM)] in IL-1 cultures was 11.47 (95% CI 7.10-15.83)-0.87 (95% CI 0.18-1.56) (P=0.0022); and (4) recombinant MMP-13 in vitro activity (15-25%; P=0.004). CONCLUSIONS: These data suggest that GA effects may be due to upregulation of IL-1Ra as well as direct inhibition of MMP-13 activity. Based on these studies, we propose that GA has potential for disease modifying properties in OA and should be evaluated in vivo in animal studies.

Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.

BACKGROUND: Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status and antipsychotic treatment following an acute illness exacerbation. METHODS: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. RESULTS: Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1ß, IL-6, and transforming growth factor-ß (TGF-ß) appeared to be state markers, as they were increased in AR and FEP (p < .001 for each) and normalized with antipsychotic treatment (p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects (p = .69). In the cerebrospinal fluid, IL-1ß was significantly decreased in schizophrenia versus controls (p = .01). CONCLUSIONS: Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1ß, IL-6, and TGF-ß) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.

Interleukin-1alpha regulates substance P expression and release in adult sensory neurons.

Nerve injury frequently results in development of chronic, dysesthetic pain and allodynia (painful sensation in response to benign stimulation). Following nerve injury, spinal cord glia become activated and secrete a number of inflammatory cytokines, including interleukin-1 (IL-1), which exists as two genetically distinct proteins, IL-1alpha and IL-1beta. To investigate whether neuropeptide expression could be altered by exposure to these cytokines, dorsal root neurons from mature rats were grown in culture and substance P (SP) expression was analyzed. IL-1alpha and IL-1beta both increased neuronal content of SP. Interestingly, IL-1alpha was significantly more efficient than IL-1beta in inducing SP expression. Cultured neurons exposed to either cytokine secreted substantially more SP with capsaicin stimulation than did control cultures, supporting a physiologic role for these inflammatory cytokines after nerve injury. However, when IL-1beta was added in combination with IL-1alpha to cultured neurons, the amount of SP expressed was significantly lower than that induced by IL-1alpha alone. Evidence is presented that both cytokines alter SP expression via the IL-1 receptor, and that the signaling pathway involves nerve growth factor (NGF) expression and transcription. In summary, IL-1alpha was significantly more efficient than IL-1beta at up-regulating SP expression than IL-1beta. Taken together, these observations suggest an important role for IL-1alpha in the events following nerve injury.

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1beta in human monocytes and multiple sclerosis.

Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1beta is present in CNS-infiltrating macrophages and microglial cells and is an important mediator of inflammation in experimental autoimmune encephalitis (EAE), the MS animal model. A natural inhibitor of IL-1beta, the secreted form of IL-1 receptor antagonist (sIL-1Ra) improves EAE disease course. In this study we examined the effects of GA on the IL-1 system. In vivo, GA treatment enhanced sIL-1Ra blood levels in both EAE mice and patients with MS, whereas IL-1beta levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contact-activated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1beta and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPS-activated monocytes, IL-1beta and sIL-1Ra production were increased in the presence of GA. These results demonstrate that, in chronic inflammatory conditions, GA enhances circulating sIL-1Ra levels and directly affects monocytes by triggering a bias toward a less inflammatory profile, increasing sIL-1Ra while diminishing IL-1beta production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.

Regulation of interleukin-1beta by the interleukin-1 receptor antagonist in the glutamate-injured spinal cord: endogenous neuroprotection.

Elevation of extracellular glutamate contributes to cell death and functional impairments generated by spinal cord injury (SCI), in part through the activation of the neurotoxic cytokine interleukin-1beta (IL-1beta). This study examines the participation of IL-1beta and its regulation by the endogenous interleukin-1 receptor antagonist (IL-1ra) in glutamate toxicity following SCI. Glutamate, glutamatergic agonists and SCI had similar effects on levels of IL-1beta and IL-1ra. Following spinal cord contusion or exposure to elevated glutamate, concentrations of IL-1beta first increased as IL-1ra decreased, and both then changed in the opposite directions. Applying the glutamate agonists NMDA and S-AMPA to the spinal cord caused changes in IL-1beta and IL-1ra levels very similar to those produced by contusion and glutamate. The glutamate antagonists MK801 and NBQX blocked the glutamate-induced changes in IL-1beta and IL-1ra levels. Administering IL-1beta elevated IL-1ra, and administering IL-1ra depressed IL-1beta levels. Infusing IL-beta into the spinal cord impaired locomotion, and infusing IL-1ra improved recovery from glutamate-induced motor impairments. We hypothesize that elevating IL-1ra opposes the damage caused by IL-1beta in SCI by reducing IL-1beta levels as well as by blocking binding of IL-1beta to its receptor. Our results demonstrate that IL-1beta contributes to glutamate damage following SCI; blocking IL-1beta may usefully counteract glutamate toxicity.

Effects of estrogen on temporal expressions of IL-1beta and IL-1ra in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation.

Anti-inflammatory action of estrogen is involved in neuroprotection but the effects of estrogen on IL-1beta and its endogenous antagonist (IL-1 ra) have not been clearly defined in the ischemic brain. This study was performed to evaluate whether estrogen affects the expression of IL-1beta or IL-1ra and the ratio of the two in the ischemic hippocampus. Rat organotypic hippocampal slices were treated with 17beta estradiol (E2, 1 nM) for 7 days, exposed to oxygen-glucose deprivation (OGD) for 30 min, and then reperfused for 72 h. CA1 neuronal death quantified by propidium iodide (PI) staining and expressions of IL-1beta and IL-1ra in slices measured by real-time PCR and Western blotting were examined. PI intensities in CA1 in slices treated with E2 were significantly reduced at 24 h and 72 h post-OGD, and IL-1beta mRNA expressions were reduced at 6 h and 24 h post-OGD. In addition, IL-1ra mRNA was significantly overexpressed and the ratio of IL-1beta to IL-1ra mRNA expression was reduced by E2 especially at 24 h. In terms of protein levels, E2 downregulated IL-1beta but upregulated IL-1ra and thereby decreased the IL-1beta/IL-1 ra ratio at 24h. These findings demonstrate that estrogen-induced protection is associated with a decrease in IL-1beta and an increase in IL-1ra expression in the ischemic hippocampus during early reperfusion periods, which suggests that modulation of IL-1beta/IL-1ra might be a part of anti-inflammatory effects of estrogen.

SB203580 enhances interleukin-1 receptor antagonist gene expression in IFN-gamma-stimulated BV2 microglial cells through a composite nuclear factor-kappaB/PU.1 binding site.

Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1alpha and IL-1beta binding to the IL-1 receptors and alleviates various inflammatory reactions. Therefore, the upregulation of IL-1ra expression is important for preventing and/or treating inflammatory diseases including many neurodegenerative diseases. This study found that SB203580, which is generally known as a p38 MAP kinase inhibitor and an anti-inflammatory agent, increased the level of IL-1ra expression in IFN-gamma-stimulated BV2 microglial cells. This effect is believed to occur through the inhibition of protein kinase B (PKB), independently of the p38 MAP kinase pathways. Further mechanistic studies using an IL-1ra promoter revealed that a composite NF-kappaB/PU.1 binding site plays an important role in this SB203580-mediated upregulation of IL-1ra. Considering that IFN-gamma is a major stimulator of the innate and adaptive immune responses, the upregulation of anti-inflammatory IL-1ra expression by SB203580 in the IFN-gamma-stimulated microglia might provide a new therapeutic modality for various inflammatory diseases of the central nervous system.

Effect of meloxicam on gingival crevicular fluid IL-1beta and IL1 receptor antagonist levels in subjects with chronic periodontitis, and its effects on clinical parameters.

The aim of the present study was to determine the effects of meloxicam after initial periodontal treatment on interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1ra) in gingival crevicular fluid (GCF) and clinical parameters in the chronic periodontitis patients. Data were obtained from 30 patients with chronic periodontitis. Fifteen chronic periodontitis patients received 7.5 mg meloxicam, and 15 patients received placebo tablets in a 1x1 regimen for 1 month. All subjects were nonsmokers and had not received any periodontal therapy. The plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment level (CAL) were recorded. The GCF was collected using a paper strip: eluted and enzyme-linked immunoabsorbent assays (ELISAs) were performed to determine the cytokine levels. The clinical data and GCF samples were obtained after periodontal therapy and 1 month after periodontal therapy. The PI, GI, PD, and GCF IL-1ra decreased significantly (p<0.05) in meloxicam group at first month when comparing the initial levels. While decrease of the PI was statistically significant in control group (p<0.05), statistically significant changes were not determined in the other clinical parameters and GCF cytokine levels (p>0.05). There were no significant differences between two groups in any of the investigated parameters. Our observations did not reveal any influence of meloxicam on levels of IL-1beta and IL-1ra in chronic periodontitis. Additional clinical studies are advisable to determine whether COX-2 selective drugs alter periodontal disease outcome with greater safety.