Monocyte Interleukin-1 Production Research Articles

0287 Effects of Sleep Restriction and Recovery on the Capacity of Glucocorticoids to Inhibit Inflammatory Marker Expression in Human Monocytes

Abstract Introduction Chronic low-grade systemic inflammation is involved in the pathogenesis of many human diseases. Common sleep patterns of restricting sleep during weekdays and catching up on sleep over the weekend induce inflammatory upregulation that may not resolve following weekend recovery sleep. We hypothesize that this sleep pattern leads to an inflammatory imbalance of markers regulating inflammatory homeostasis, including inflammatory markers (eg, interleukin-6 (IL-6) and cyclooxygenase 2 (COX-2)) and markers of counter-inflammation (eg, glucocorticoids (GCs)). The enzyme COX-2 is involved in prostaglandin synthesis and is the target of pain-relieving nonsteroidal anti-inflammatory drugs (NSAIDs). GCs are used in the treatment of many inflammatory diseases, including severe acute infection with SARS-CoV-2. We investigated if sleep restriction impairs the capacity of GCs to inhibit inflammatory COX-2 expression in a preliminary dataset. Methods The present preliminary dataset (N=6, 2F/4M) derives from an ongoing randomized controlled within-subjects trial consisting of three 11-day in-hospital protocols (2 restricted sleep arms, 1 control sleep arm). The ongoing study is blinded for administration of placebo or aspirin under sleep restriction. Under restricted sleep conditions, 2 nights of baseline sleep (8h/night) were followed by 5 nights of restricted sleep (4h/night), concluding with 3 nights of recovery sleep (8h/night). In the control condition, participants could sleep 8h/night throughout the entire protocol. Blood samples were taken after baseline sleep, after 5 nights of restricted or control sleep, and after 2 nights of recovery sleep. Data were analyzed using generalized linear mixed models. Results Sleep restriction was associated with decreased capacity of GCs to inhibit COX-2 expression in monocytes (p<.01) and has the expected inflammatory effect on IL-6 production in monocytes (p<.01). Moreover, sleep restriction has lasting inflammatory effects as shown in increased inflammation following 2 nights of recovery sleep (p<.01). Conclusion In conclusion, the present preliminary analysis suggests that in patients treated with GCs, sleep restriction potentially reduces their effectiveness in controlling inflammation, thus contributing to increased inflammation-related morbidity. Sample collection and data analysis is ongoing. Support (If Any) NIH/NHLBI R01-HL136310; NIH/NCRR UL1-RR02758, M01-RR01032; German Research Foundation (DFG) EN1291/1-1.

Characterization of Circulating IL-10-Producing Cells in Septic Shock Patients: A Proof of Concept Study.

Sepsis is a worldwide health priority characterized by the occurrence of severe immunosuppression associated with increased risk of death and secondary infections. Interleukin 10 (IL-10) is a potent immunosuppressive cytokine which plasma concentration is increased in septic patients in association with deleterious outcomes. Despite studies evaluating IL-10 production in specific subpopulations of purified cells, the concomitant description of IL-10 production in monocytes and lymphocytes in septic patients’ whole blood has never been performed. In this pilot study, we characterized IL-10 producing leukocytes in septic shock patients through whole blood intracellular staining by flow cytometry. Twelve adult septic shock patients and 9 healthy volunteers were included. Intracellular tumor necrosis factor-α (TNFα) and IL-10 productions after lipopolysaccharide stimulation by monocytes and IL-10 production after PMA/Ionomycine stimulation by lymphocytes were evaluated. Standard immunomonitoring (HLA-DR expression on monocytes, CD4+ T lymphocyte count) of patients was also performed. TNFα expression by stimulated monocytes was reduced in patients compared with controls while IL-10 production was increased. This was correlated with a reduced monocyte HLA-DR expression. B cells, CD4+, and CD4- T lymphocytes were the three circulating IL-10 producing lymphocyte subsets in both patients and controls. No difference in IL-10 production between patients and controls was observed for B and CD4- T cells. However, IL-10 production by CD4+ T lymphocytes significantly increased in patients in parallel with reduced CD4+ T cells number. Parameters reflecting altered monocyte (increased IL-10 production, decreased HLA-DR expression and decreased TNFα synthesis) and CD4+ T lymphocyte (increased IL-10 production, decreased circulating number) responses were correlated. Using a novel technique for intracellular cytokine measurement in whole blood, our results identify monocytes and CD4+ T cells as the main IL-10 producers in septic patients’ whole blood and illustrate the development of a global immunosuppressive profile in septic shock. Overall, these preliminary results add to our understanding of the global increase in IL-10 production induced by septic shock. Further research is mandatory to determine the pathophysiological mechanisms leading to such increased IL-10 production in monocytes and CD4+ T cells.

Estrogen signaling differentially alters iron metabolism in monocytes in an Interleukin 6-dependent manner

The ability of monocytes to release or sequester iron affects their role in cancer and inflammation. Previous work has shown that while IL-6 upregulates hepcidin synthesis and enhances iron sequestration, E2 reduces hepcidin synthesis and increases iron release. Given that E2 upregulates IL-6 production in monocytes, it is likely that the exact effect of E2 on iron metabolism in monocytes is shaped by its effect on IL-6 expression. To address this issue, the expression of key iron regulatory proteins was assessed in E2-treated U937, HuT-78, THP-1 and Hep-G2 cells. Iron status was also evaluated in U937 cells treated with the ERα agonist PPT, the ER antagonist ICI-182780, dexamethasone + E2, IL-6 + E2 and in IL-6-silenced U937 cells. E2 treatment reduced hepcidin synthesis in HuT-78, THP-1 and Hep-G2 cells but increased hepcidin synthesis and reduced FPN expression in U937 cells. E2-treated U937 cells also showed reduced HIF-1α and FTH expression and increased TFR1 expression, which associated with increased labile iron content as compared with similarly treated Hep-G2 cells. While treatment of U937 cells with interleukin 6 (IL-6) resulted in increased expression of hepcidin, dexamethasone treatment resulted in reduced hepcidin synthesis relative to E2- or dexamethasone + E2-treated cells; IL-6 silencing also resulted in reduced hepcidin synthesis in U937 cells. Lastly, while iron depletion resulted in increased cell death in U937 cells, E2 treatment resulted in enhanced cell survival and reduced apoptosis. These findings suggest that E2 differentially alters iron metabolism in monocytes in an IL-6 dependent manner.

GROWTH DIFFERENTIATION FACTOR 15 IS CORRELATED TO MARKERS OF IMMUNOSENESCENCE IN MONOCYTES

Immunosenescence is an age-associated decrease in function of immune cells precipitated by a variety of mechanisms and affecting nearly every immune cell subset. In myeloid cell subsets, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we have described an aging effect on several functions indicating immunosenescence in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide (LPS). We hypothesized that circulating factors altered by the aging process underly these changes. Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily that has known anti-inflammatory effects in macrophages and has recently been shown to be highly differentially expressed during aging. We used biobanked serum and plasma samples to assay circulating GDF-15 levels in subjects from our previous studies and examined correlations between GDF-15 levels and monocyte mitochondrial function and inflammatory responses. Monocyte interleukin-6 production due to LPS stimulation was negatively correlated to plasma GDF-15 levels (p = 0.046). Additionally, serum GDF-15 was positively correlated to circulating CD16+ monocyte proportions (p = 0.021) and negatively correlated to monocyte mitochondrial respiratory capacity (p < 0.001). Therefore, our data suggest that GDF-15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence, and thus is an attractive candidate for therapeutic intervention to ameliorate this.

Induction of Interleukin 10 by Borrelia burgdorferi Is Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling.

Host genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacterium Borrelia burgdorferi C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated with B. burgdorferi produce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences of B. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.

Immunomodulatory effects of Lippia sidoides extract: induction of IL-10 through cAMP and p38 MAPK-dependent mechanisms.

Lippia sidoides is an aromatic shrub that grows wild in the northeastern region of Brazil. In local traditional medicine, the aerial portions of this species are used as anti-infectives, antiseptics, spasmolytics, sedatives, hypotensives, and anti-inflammatory agents. In this research, we evaluate the potential immunological properties of Lippia extract through in vitro analysis of its ability to modulate intracellular cyclic adenosine monophosphate (cAMP) levels and interleukin-10 (IL-10) production. These results show that Lippia extract increases intracellular cAMP through the inhibition of phosphodiesterase activity. They also demonstrate that Lippia extract increases IL-10 production in THP-1 monocytes through both an increase in intracellular cAMP and the activation of p38 MAPK. These results suggest that the Lippia-mediated inhibition of phosphodiesterase activity and the subsequent increase in intracellular cAMP may explain some of the biological activities associated with L. sidoides. In addition, the anti-inflammatory activity of L. sidoides may also be due, in part, to its ability to induce IL-10 production through the inhibition of cyclic nucleotide-dependent phosphodiesterase activity and by its activation of the p38 MAPK pathway.

Insoluble immune complexes are most effective at triggering IL-10 production in human monocytes and synergize with TLR ligands and C5a

Purpose In systemic lupus erythematosus (SLE), a disease of immune complex (IC) deposition, interleukin-10 (IL-10) is thought to promote B-lymphocyte hyperactivity and autoantibody production. Both ICs and Toll-like receptor (TLR) ligands have been shown to stimulate the production of IL-10 by human monocytes. Using an in vitro model, we studied how IC solubility, complement activation products, and TLR ligands could affect IL-10 production by human monocytes stimulated with ICs. Methods Human monocytes were stimulated with soluble or insoluble heat-aggregated human IgG with or without TLR ligands or C5a. Cytokine levels in cell culture supernatants were measured by ELISA. To study cytokine signaling, cell lysates were analyzed by Western blot for total or tyrosine-phosphorylated STAT3. Results Insoluble ICs were most effective at stimulating production of IL-10, and costimulation LPS enhanced synthesis of IL-10. In addition, stimulation with insoluble ICs together with C5a enhanced the production of IL-10 by 2–4 fold in either the presence or absence of TLR ligands. Increased STAT3 phosphorylation correlated temporally with enhanced IL-10 production and was reduced by an IL-10 receptor blocking antibody, suggesting that IL-10 was responsible for observed STAT3 phosphorylation. Conclusions Because the immune deposits of SLE are, by definition, insoluble; and because IL-10 is thought to be important for B-cell hyperactivity and autoantibody production, these observations provide a critical link, bridging current views of B-cell hyperactivity with the early concept that SLE may arise from defective clearance of immune complexes.

Modulation of endotoxin stimulated interleukin-6 production in monocytes and Kupffer cells by S-adenosylmethionine (SAMe)

Interleukin-6 (IL-6) is a multifunctional cytokine having primarily anti-apoptotic and anti-inflammatory effects. Recent reports have documented that IL-6 plays a key role in liver regeneration. Intracellular deficiency of S-adenosylmethionine (SAMe) is a hallmark of toxin-induced liver injury. Although the administration of exogenous SAMe attenuates liver injury, its mechanisms of action are not fully understood. Here we investigated the effects of exogenous SAMe on IL-6 production in monocytes and Kupffer cells. RAW 264.7 cells, a murine monocyte cell line, and isolated rat Kupffer cells were stimulated with lipopolysaccharide (LPS) in the absence or presence of exogenous SAMe. IL-6 production was assayed by ELISA and intracellular SAMe concentrations were measured by HPLC. We have found that exogenous SAMe administration enhanced both IL-6 protein production and gene expression in LPS-stimulated monocytes and Kupffer cells. Cycloleucine (CL), an inhibitor for extrahepatic methionine adenosyltransferases (MAT), inhibited LPS-stimulated IL-6 production. The enhancement of LPS-stimulated IL-6 production by SAMe was inhibited by ZM241385, a specific antagonist of adenosine (A 2) receptor. Our results demonstrate that SAMe administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-6 production.

S-adenosylmethionine (AdoMet) modulates endotoxin stimulated interleukin-10 production in monocytes.

IL-10 is produced by a large variety of cells including monocytes, macrophages, B and T lymphocytes, as well as natural killer cells and is an important suppressor for both immunoproliferative and inflammatory responses. IL-10 exerts antifibrotic effects in the liver, and decreased monocyte synthesis of IL-10 is well documented in alcoholic cirrhosis. Intracellular deficiency of S-adenosylmethionine (AdoMet) is a hallmark of toxin-induced liver injury. Although the administration of exogenous AdoMet attenuates this injury, the mechanisms of its actions are not fully established. This study was performed to investigate the effect of exogenous AdoMet on IL-10 production in LPS-stimulated RAW 264.7 cells, a murine macrophage cell line. Our results demonstrated that exogenous AdoMet administration enhanced both protein production and gene expression of IL-10 in RAW 264.7 cells. Ethionine, an inhibitor for methionine adenosyltransferases, inhibited LPS-stimulated IL-10 both at the protein and mRNA levels. Exogenous AdoMet increased the intracellular cAMP concentration as early as 3 h and continued for 24 h after AdoMet treatment; however, the inhibitors for both adenylyl cyclase and PKA did not significantly affect IL-10 production. On the basis of these results, we conclude that AdoMet administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-10 production.

Different mechanisms are utilized by HIV-1 Nef and staphylococcal enterotoxin A to control and regulate interleukin-10 production

Interleukin-10 (IL-10) plays an important immunopathogenic role in immunologic diseases, especially in HIV infection and atopic dermatitis. The control and regulatory mechanisms of IL-10 production have not been described in these diseases. Recently, we demonstrated that HIV-1 Nef induces IL-10 production in monocytes and that staphylococcal enterotoxin A (SEA) induces IL-10 production in T-lymphocytes. Here we show that Nef-induced IL-10 production and mRNA expression are strongly blocked by rapamycin, but are not blocked by cyclosporin (CsA) or FK506. Conversely, we show that CsA and FK506 completely inhibit SEA-induced IL-10 protein production and mRNA expression. The results of this study demonstrate that IL-10 production by Nef and SEA is controlled and regulated by different mechanisms.

Effect of anti-inflammatory medication on monocyte response to titanium particles.

Cytokines produced by macrophages in the periprosthetic membranes surrounding joint replacements have been implicated as causal agents in osteolysis and prosthetic loosening. The present study characterizes the response of human peripheral blood monocytes to titanium particles. Monocytes were obtained from donated blood and were cultured in the presence of different-sized titanium particles. Exposure to titanium-aluminum-vanadium particles significantly changed the release of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 (IL-1), whereas there was no significant effect on the release of prostaglandin E(2) (PGE(2)). When monocytes were cultured with particles, the titanium alloy particles induced significantly more release of TNF-alpha and less IL-1 secretion. Ciprofloxacin inhibited production of TNF-alpha, IL-6, IL-1, and PGE(2) in human monocytes exposed to titanium particles. In contrast to ciprofloxacin, indomethacin was not a potent inhibitor of TNF-alpha production but potentiated IL-6 production in titanium-stimulated monocytes. Indomethacin had no effect on the production of IL-1 and was a potent inhibitor of PGE(2) production in titanium-stimulated monocytes. Pentoxifylline had an inhibitor effect on TNF-alpha production in titanium-stimulated monocytes. Pentoxifylline potentiated IL-6 and IL-1 production in monocytes exposed to titanium particles and had a biphasic effect on the PGE(2) production. The results of this study support our hypothesis that human monocytes release bone resorption mediators after in vitro exposure to TiAlV alloy particles. The results also demonstrate the differences of bone-resorbing mediators in response to different wear particle size. The pharmacologic agents (ciprofloxacin, pentoxifylline, and indomethacin) that can modulate the release of bone resorbing mediators such as PGE(2), TNF-alpha, IL-1, and IL-6 release from human monocytes. The results help to elucidate the differences in cellular response to wear particles but may not be directly transposed to the human situation.

Involvement of adenylate cyclase and p70(S6)-kinase activation in IL-10 up-regulation in human monocytes by gp41 envelope protein of human immunodeficiency virus type 1.

Our previous results show that recombinant gp41 (aa565-647), the extracellular domain of HIV-1 transmembrane glycoprotein, stimulates interleukin-10 (IL-10) production in human monocytes. The signal cascade transducing this effect is not yet clear. In this study, we examined whether gp41-induced IL-10 up-regulation is mediated by the previously described synergistic activation of cAMP and NF-kappaB pathways. gp41 induced cAMP accumulation in monocytes in a time- and concentration-dependent manner and the adenylate cyclase inhibitor SQ 22536 suppressed gp41-induced IL-10 production in monocytes. In contrast, gp41 failed to stimulate NF-kappaB binding activity in as much as no NF-kappaB bound to the main NF-kappaB-binding site 2 of the IL-10 promoter after addition of gp41. We also examined the involvement of other signal transduction pathways. Specific inhibitors of p70(S6)-kinase (rapamycin), and Gi protein (pertussis toxin), prevented induction of IL-10 production by gp41 in monocytes, while inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase) (wortmannin) and mitogen-activated protein kinase (MAPK) pathway (PD 98059) did not. Thus HIV-1 gp41-induced IL-10 up-regulation in monocytes may not involve NF-kappaB, MAPK, or PI 3-kinase activation, but rather may operate through activation of adenylate cyclase and pertussis-toxin-sensitive Gi/Go protein to effect p70(S6)-kinase activation.

Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.

To study the in vitro effect of testosterone on anti-DNA antibody production in peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE) in order to elucidate its regulatory role in SLE. PBMC from SLE patients were cultured with testosterone. IgG anti-double-stranded DNA (anti-dsDNA) antibody, total IgG, and cytokine activity in the supernatants were measured by enzyme-linked immunosorbent assay. Testosterone suppressed both IgG anti-dsDNA antibody and total IgG production in PBMC from SLE patients. Antibody production in B cells was also suppressed by testosterone, although the magnitude of its effect on B cells was lower than that on PBMC. Interleukin-6 (IL-6) partially restored the testosterone-induced decrease in antibody levels in PBMC. Testosterone reduced IL-6 production in monocytes. These results suggest that testosterone may directly suppress anti-DNA antibody production in PBMC from SLE patients by inhibiting B cell hyperactivity and, indirectly, by down-regulating IL-6 production in monocytes. These results support the therapeutic effects of testosterone on SLE.

HIV-1 recombinant gp41 induces IL-10 expression and production in peripheral blood monocytes but not in T-lymphocytes

The effects of recombinant gp41 (rgp41) protein of the human immunodeficiency virus type 1 (HIV-1) on interleukin 10 (IL-10) expression and production using human peripheral blood mononuclear cells was investigated. Expression of IL-10 mRNA was demonstrated within 3 h of cell exposure to endotoxin-free rgp41 by RT-PCR and Northern blot analyses in a time- and dose-dependent manner. IL-10 protein was detected in the supernatants of peripheral blood mononuclear cells following stimulation with rgp41 also in a dose dependent manner. Fractionation of peripheral blood mononuclear cells showed that purified monocytes but not purified T-lymphocytes induced expression of IL-10 mRNA by rgp41. Recombinant HIV-1 gp120 exhibits similar influences on the induction of IL-10. These results indicate that both of these components of envelope proteins may play an important role in HIV related immunomodulation by influencing regulatory functions of monocytes and macrophages.

FK506 and Cyclosporin A Enhance IL-6 Production in Monocytes: A single-Cell Assay

The effect of FK506 and cyclosporin A (CsA) on the production of interleukin 6 (IL-6) in adherent monocytes was studied at a single-cell level by the avidinbiotin- peroxidase complex methods. The percentage of IL-6-producing monocytes increased when stimulated with lipopolysaccharide (LPS) at concentrations between 10 ng/ml and 10 μg/ml, in a dose dependent manner. Both FK506 and CsA enhanced the percentage of IL-6- producing monocytes stimulated with 100 pg/ml-1 μg/ml of LPS up to values near those obtained with 10 μg/ml of LPS. The enhancement by FK506 and CsA was not seen when monocytes were stimulated with a high concentration of LPS (10 μg/ml). When monocytes were stimulated with a low concentration of LPS (10 ng/ml), FK506 and CsA enhanced IL-6 production in a dose dependent manner, at a drug concentration of 0.12 nM–1.2 μM (0.1–1 000 ng/ml) for FK506 and 0.83 nM–8.3 μM (1–10 000 ng/ml) for CsA. The optimal effect of FK506 was achieved at a concentration 7-fold lower than that of CsA. In contrast, production of turnout necrosis factor-α (TNFα and interleukin 1β (IL-1β) was slightly suppressed by FK506 and CsA at the concentrations tested. Moreover, pretreatment of monocytes with FK506 and CsA had a significant enhancing effect on LPS-induced IL-6 production, while treatment with FK506 or CsA after LPS stimulation had no effects on IL-6 production, suggesting that the enhancing effect of each drug is exerted before LPS stimulation or at an early stage of the post-receptor pathway after LPS stimulation. These experiments demonstrate that FK506 and CsA can selectively enhance IL-6 production in monocytes under certain conditions in vitro and, possibly, also in vivo.

Inhibition of interferon-γ- and phorbol ester-induced HLA-DR and interleukin-1 production by the expression of a transfected poly(ADP-ribose) synthetase gene in human leukemia THP-1 cells

We have examined a correlation between an expression level of poly(ADP-ribose) synthetase gene and the stage of monocytic differentiation. We ?????? three human leukemia cell lines, U937, THP-1, and J111, whose differentiation stage was characterized by nitroblue tetrazolium reduction activity, non-specific esterase activity, phagocytic activity and a cell surface differentiation. When THP-1 cells were treated with either interferon-γ or phorbol ester, mRNA level of the synthetase decreased and HLA-DR or interleukin-1 was induced, respectively. We transfected expression plasmid of the exogenous synthetase gene to examine whether the down-regulation of the synthetase is a necessary step to induce these proteins. An expression of the exogenous synthetase gene inhibited the interferon-γ- and phorbol ester-dependent induction of HLD-DR and interleukin-1. The results suggest that down-regulation of the synthetase may be a signal mediator of immunological response such as HLA-DR or interleukin-1 production in monocytes.

The effect of gold treatment on monocyte interleukin-1 production in rheumatoid arthritis

Monocyte interleukin-1 (IL-1) production in vitro was studied in 49 patients with rheumatoid arthritis (RA) and 31 controls. Twenty-six of the RA patients were studied prospectively for up to 12 months after beginning chrysotherapy. About half of the patients (group 1) exhibited pretreatment levels of monocyte IL-1 secretion (as measured by bioassay or B-IL-1) significantly higher than that of the controls. Immunoreactive IL-1 (IR-IL-1) levels, however, were similar to controls. Clinical improvement in this group of patients was modest and transient but could be associated with a fall in the level of IL-1 (B-IL-1 and IR-IL-1) secretion. Other RA patients (group 2) appeared to have normal or reduced pretreatment levels of IL-1 secretion. Chrysotherapy resulted in significant clinical improvement within 3 months, and this was associated with an increase in IL-1 (both B-IL-1 and IR-IL-1) secretion by the patients' blood monocytes to normal or supranormal levels. Thus these two groups of RA patients (which differed only in the average duration of disease) had different prognoses in relation to chrysotherapy and the effect of chrysotherapy-induced remission on monocyte IL-1 secretion was opposite. These results suggest that monocyte IL-1 production in vitro reflects changes secondary to the anti-rheumatic effects of chrysotherapy.

Comparison of the effect between leukotriene B4 and leukotriene B5 on the induction of interleukin 1-like activity and calcium mobilizing activity in human blood monocytes

Leukotriene B4 (LTB4), one of 5-lipoxygenase (5-LO) products of arachidonic acid, was reported to be more potent than leukotriene B5 (LTB5), one of 5-LO products of eicosapentaenoic acid, in the activation of neutrophil functions through the differential potency between these leukotrienes in calcium mobilization. So we compared the effect of LTB4 and LTB5 on the induction of interleukin 1 (IL-1)-like activity and calcium mobilization in human blood monocytes. LTB4 significantly augmented IL-1-like activity in monocytes, however, LTB5 had no significant effect. Also LTB4 was apparently more potent than LTB5 in inducing calcium mobilization in fura-2-loaded monocytes. IL-1 production in monocytes was reported to be partly dependent on cytosolic free calcium. These results, therefore, may indicate that the different activity between LTB4 and LTB5 in the enhancement of IL-1-like activity could be partly ascribed to the different potency in inducing calcium mobilization between LTB4 and LTB5 in human blood monocytes.

The role of interleukin-1 in postmenopausal bone loss

Interleukin-1 (IL-1), a cytokine best known for its ability to stimulate lymphocyte proliferations, has recently been shown to stimulate bone resorption and modulate bone formation in vivo. Consequently, the authors have devised a series of studies to investigate the relationship between bone remodeling, menopause, and monocyte IL-1-secretion. In a first study, monocytes from osteoporotic patients were found to produce more IL-1 than monocytes from control subjects. IL-1 activity was also found to reflect histomorphometric indices of bone formation, but not of bone resorption. In a second study, devised to assess the effect of menopause on the relationship between IL-1 and bone turnover, a significant correlation was found between IL-1 and BGP in premenopausal osteoporotic women and osteoporotic men, but not in both postmenopausal osteoporotic subjects and normal subjects of either sex. In a third study, IL-1 from untreated postmenopausal women was found to be higher than in either untreated premenopausal or estrogen/progesterone-treated postmenopausal women. A significant negative correlation was found between IL-1 and years since menopause in both the healthy and osteoporotic postmenopausal women. Premenopausal IL-1 levels were achieved within eight years of menopause in the healthy but not in the osteoporotic subjects. In osteoporotic women, high IL-1 levels were evident as long as 15 years after menopause. IL-1 also correlated inversely with mineral density as measured by quantitative computer tomography. In prospective study, treatment with estrogen/progesterone caused a significant increase in IL-1 activity. This data indicates that monocyte IL-1 production mirrors the rate of bone turnover in both the healthy and osteoporotic patient, and that alteration in IL-1 production may underlie the postmenopausal acceleration of bone loss and its inhibition by ovarian steroids.

Effects of prostaglandins and cAMP levels on monocyte IL-1 production

The effects of prostaglandin E2 (PGE2), as well as other cAMP-elevating agents, on the in vitro production of interleukin-1 (IL-1) by human monocytes (HM) were examined. Exposure to E. coli lipopolysacharide (LPS) resulted in a dose- and time-dependent increase of IL-1 activity in monocytes culture supernatants. Maximal levels of secreted IL-1 in response to 10 ng LPS/ml were obtained at 18 h. PGE1, PGE2, cholera toxin (CT) and the phosphodiesterase inhibitor, isobutylmethylxanthin (IBMX), when added with LPS, resulted in a dose-dependent increase in cellular cAMP and in secreted IL-1. Maximal levels of secreted IL-1 were 2.5-5.0-fold over LPS alone. When CT or PGE2 was added with IBMX a further increase was observed. These agents exhibited marginal effect on cell-associated IL-1. Maximum cAMP levels was achieved at 10 min in response to either PGE1 or PGE2 and returned to near basal levels after 18 h. While PGE1 elevated cAMP to a larger extent than PGE2 (58- vs. 30-fold) the latter resulted in a higher levels of secreted IL-1. Elevated cAMP persisted throughout the entire culture period in response to CT (4-6-fold) or IBMX (7-fold). Thus, we conclude that in adherent HM, IL-1 production is potentiated and not inhibited by prostaglandins or agents that elevate cellular cAMP.