Levels of MCP-1 and GM-CSF mRNA correlated with inflammatory cytokines mRNA levels in experimental autoimmune myocarditis in rats

Infiltration of monocytes and T cells is known to be an essential trigger for the progression of experimental autoimmune myocarditis (EAM) in rats. Monocyte chemotactic protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were shown to mediate the migration of monocytes and T cells into inflammatory sites and to proliferate monocytes. Thus, we evaluated levels of MCP-1 and GM-CSF mRNA in the myocardium of EAM in rats using a real time quantitative PCR method. We also examined the correlation of MCP-1 or GM-CSF mRNA levels with those of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in the same lesion. Levels of MCP-1, GM-CSF, TNF-alpha, IL-1beta and IL-6 mRNA increased with the progression of myocarditis which was accompanied by the accumulation of ED-1 positive cells. The MCP-1 and GM-CSF mRNA levels were positively correlated with TNF-alpha, IL-1beta and IL-6 mRNA levels in the same lesion of EAM. We also demonstrated that serum MCP-1 concentrations were increased during the active stage of EAM, and were correlated with MCP-1 mRNA levels in the myocardium of each rat. These findings suggest that elevated MCP-1 and GM-CSF may associate with the migration and proliferation of monocytes/macrophages in EAM. Thus, MCP-1 and GM-CSF may play an important role in the progression of EAM.     

IL-1beta, IL-6 and TNF-alpha in synovial fluid of patients with non-gonococcal septic arthritis

Interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are the main proinflammatory cytokines responsible for the inflammatory process and cartilage destruction of inflammatory arthropathies. The present study sequentially measured the concentrations of these cytokines and their proportions of detectable levels in the synovial fluid (SF) of 23 patients with non-gonococcal (GC) septic arthritis before and after treatment. Persistently high concentrations and proportions of IL-6 and TNF-alpha were found up to day 7 of treatment, while SF IL-1beta concentration declined significantly after day 7 (p = 0.036). SF IL-1beta and TNF-alpha correlated with each other significantly and with SF WBC counts (p < 0.01). Positive correlations between SF IL-1beta concentration and joint effusion (p < 0.01) and between SF TNF-alpha concentration and joint tenderness (p < 0.001) were observed. SF IL-1beta and TNF-alpha were significantly higher in patients with local complications of septic arthritis. In conclusion, high levels of IL-1beta, IL-6 and TNF-alpha were detected in SF of patients with non-GC septic arthritis. Only IL-1beta decreased significantly after day 7 of treatment, but IL-6 and TNF-alpha concentrations were persistently high. SF IL-1beta and TNF-alpha may be useful in predicting the outcome and complications of patients with this disease.     

Effects of Listeria monocytogenes and Yersinia enterocolitica on cytokine gene expression and release from human polymorphonuclear granulocytes and epithelial (HEp-2) cells.

The gene expression and cytokine release of the proinflammatory cytokines interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) after infection of human epithelial cells (HEp-2 cells) and polymorphonuclear granulocytes (PMNs) were investigated by using isogenic pairs of Listeria monocytogenes and Yersinia enterocolitica strains. By polymerase chain reaction-assisted mRNA amplification and RNA dot blot analysis, we showed that PMNs and HEp-2 cells expressed enhanced levels of mRNA encoding IL-1 beta, IL-6, and TNF-alpha after bacterial infection. Concomitant with the enhanced mRNA level, an increased secretion rate of IL-1 beta, IL-6, and TNF-alpha from PMNs as assessed by enzyme-linked immunosorbent assay was observed. HEp-2 cells after infection also released IL-6 and TNF-alpha into the cell supernatant, while no IL-1 beta release was detected. Cellular coincubation experiments were carried out with Transwell chambers. Our studies revealed that the coculture of PMNs and HEp-2 cells led to an increased IL-1 beta and IL-6 release. In contrast, after infection with the invasive bacteria, reduced levels of TNF-alpha were measured. Our data show that PMNs secrete the proinflammatory cytokines IL-1 beta, IL-6, and TNF-alpha within some hours after infection with L. monocytogenes and Y. enterocolitica and that cellular interactions with epithelial cells alone via soluble mediators influence the net amount of released proinflammatory cytokines.     

Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats

Hypoxic injury in the perinatal period results in periventricular white matter (PWM) lesions with axonal damage and oligodendroglial loss. It also alters macrophage function by perpetuating expression of inflammatory mediators. Relevant to this is the preponderance of amoeboid microglial cells (AMC) characterized as active macrophages in the developing PWM. This study aimed to determine if AMC produce proinflammatory cytokines that may be linked to the oligodendroglial loss observed in hypoxic PWM damage (PWMD). Wistar rats (1 day old) were subjected to hypoxia, following which upregulated expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), TNF receptor 1 (TNF-R(1)) and IL-1 receptor 1 (IL-1R(1)) was observed. This was coupled with apoptosis and expression of TNF-R(1) and IL-1R(1) in oligodendrocytes. Primary cultured microglial cells subjected to hypoxia (3% oxygen, 5% CO(2) and 92% nitrogen) showed enhanced expression of TNF-alpha and IL-1beta. Furthermore, mitogen-activated protein (MAP) kinase signaling pathway was involved in the expression of TNF-alpha and IL-1beta in microglia subjected to hypoxia. Our results suggest that following a hypoxic insult, microglial cells in the neonatal rats produce inflammatory cytokines such as TNF-alpha and IL-1beta via MAP kinase signaling pathway. These cytokines are detrimental to oligodendrocytes resulting in PWM lesion.     

Cytokines in nasopharyngeal secretions; evidence for defective IL-1 beta production in children with recurrent episodes of acute otitis media.

The host-parasite relationship in the nasopharynx of young children with bacterial colonization and antigen uptake in the mucosa and lymphatic tissue provides an opportunity to investigate infectious/inflammatory processes and responses. IL-1 beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were analysed in nasopharyngeal secretions and serum from children with or without recurrent episodes of acute otitis media, from healthy adults and adults with or without recurrent episodes of acute otitis media, from healthy adults and adults with hypogammaglobulinaemia or selective deficiency of IgG3. Nasopharyngeal secretions generally contained substantial amounts of IL-1 beta, IL-6 and TNF-alpha. In contrast, IL-1 beta, IL-6 and TNF-alpha were not detectable in sera on the same occasion. Children were found to have higher levels of IL-1 beta, IL-6 and TNF-alpha than healthy adults and than adults with immunodeficiency. High levels of IL-1 beta were associated with low or undetectable levels of IL-6 and TNF-alpha, whereas the opposite pattern was seen in association with low levels of IL-1 beta. This was especially true for children with recurrent episodes of acute otitis media (RAOM). In children with nasopharyngeal colonization with Haemophilus influenzae, significantly higher levels of IL-1 beta, IL-6 and TNF-alpha (P = 0.0001, respectively) were found compared with non-colonized children. Notably, the RAOM children exhibited significantly lower levels of IL-1 beta, IL-6, and TNF-alpha in nasopharyngeal secretions (P = 0.0001, 0.01 and 0.0001, respectively) than healthy children. These results demonstrate local production of inflammatory cytokines in nasopharynx, related to bacterial colonization, and suggest that children with RAOM are poor nasopharyngeal cytokine producers.     

Antimonial therapy induces circulating proinflammatory cytokines in patients with cutaneous leishmaniasis

The objective of this study was to evaluate the association between antimonial therapy and circulating levels of proinflammatory cytokines in patients with cutaneous leishmaniasis (CL). Patients were treated with conventional chemotherapy by using pentavalent antimonium salts (Glucantime) for 3 weeks. Circulating plasma levels of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) were determined for CL patients and healthy subjects before and 3 weeks after the treatment was started. Plasma IL-1beta, IL-6, IL-8, and TNF-alpha levels were significantly higher for pretreatment CL patients than for healthy subjects. Proinflammatory cytokines significantly increased after 21 days postinfection compared to levels for the pretreatment patients. These increments were approximately 3-fold for IL-1beta and TNF-alpha levels, 10-fold for IL-6 levels, and 20-fold for IL-8 levels in patients with CL. Taken together these results indicate that circulating proinflammatory cytokine levels were increased in patients with CL as a consequence of host defense strategies, and antimonial therapy may induce these cytokines by affecting the macrophage or other components of the host defense system.     

Synthesis and regulation of accessory/proinflammatory cytokines by intestinal epithelial cells.

Intestinal epithelial cells (IEC) have been shown to act as antigen-presenting cells (APC) in vitro and may have this capacity in vivo. In order to determine whether IEC, like other APC, are able to produce accessory cytokines which may play a role in T cell activation, we assessed the accessory cytokine profile of IEC constitutively or after stimulation. We measured expression, production and regulation of accessory cytokines (IL-1 beta, IL-6, tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) by the presence of mRNA as well as secreted protein. Freshly isolated IEC from surgical specimens were cultured in the presence or absence of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), IL-1 beta or TNF-alpha. mRNA was assessed by a specific RNAse protection assay which controlled for contaminating cell populations while protein secretion was measured by ELISA (IL-1) or bioassay (TNF and IL-6). Neither IL-1 beta nor TNF-alpha were detectable in cultured IEC supernatants, supporting the lack of macrophage contamination. All IEC spontaneously secreted IL-6 at levels comparable to those of macrophages. IEC IL-6 mRNA also increased approximately 200-fold during the first 24 h of culture. LPS, IFN-gamma or TNF-alpha had no effect on spontaneous IL-6 production, and neither resulted in the secretion of IL-1 beta or TNF-alpha. However, IL-1 beta up-regulated IL-6 synthesis by 6-7-fold. IEC express a profile of cytokine mRNAs distinct from conventional APC (low level constitutive IL-6 expression but no detectable IL-1 beta, TGF-beta or TNF-alpha), adding to their uniqueness as APC.     

Role of Tumor Necrosis Factor Alpha, Interleukin-1β, and Interleukin-6 in a Mouse Model of Group B Streptococcal Arthritis

Intravenous inoculation of CD1 mice with 10(7) CFU of type IV group B Streptococcus (GBS IV) results in a high incidence of diffuse septic arthritis. In this study the roles of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in articular pathology were evaluated. Cytokine levels were quantified in the serum and joints by enzyme-linked immunosorbent assay in mice injected with GBS IV and tested or not tested with pentoxifylline (PTF), a methylxanthine that affects cytokine production. PTF was administered intraperitoneally at a dose of 1 mg/mouse (50 mg/kg of body weight) 1 h after GBS infection and then at 24-h intervals for 4 days. High levels of IL-1beta and IL-6, but not TNF-alpha, were detected in the joints of mice injected with GBS IV from 5 to 15 days after infection, when articular lesions were most frequent and severe. IL-1beta and IL-6 concentrations in the joints significantly (P < 0.001) exceeded those detected in the serum, confirming a strong local production. PTF treatment resulted in a strong reduction of cytokine production and in a marked decrease in both the incidence and severity of arthritis. Inoculation of exogenous murine recombinant IL-1beta or IL-6 in mice treated with GBS IV plus PTF resulted in an incidence and severity of articular lesions similar to those obtained with inoculation of GBS IV alone. No significant effect was obtained with TNF-alpha administration. These data show a strong involvement of IL-1beta and IL-6, but not TNF-alpha, in the pathogenesis of GBS arthritis.     

Impaired expression of indoleamine 2, 3-dioxygenase in monocyte-derived dendritic cells in response to Toll-like receptor-7/8 ligands

The endogenous cannabinoid system plays an important role in regulating the immune system. Modulation of endogenous cannabinoids represents an attractive alternative for the treatment of inflammatory disorders. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme catalysing degradation of the endogenous cannabinoid anandamide, and AM404, an inhibitor of anandamide transport, on lipopolysaccharide (LPS)-induced increases in plasma cytokine levels in rats. Both URB597 and AM404 potentiated the LPS-induced increase in plasma tumour necrosis factor-alpha (TNF-alpha) levels. The peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, GW9662, attenuated the AM404-induced augmentation of TNF-alpha levels. Furthermore, the selective cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630 respectively, and the transient receptor potential vanilloid receptor-1 (TRPV1) antagonist, SB366791, reduced LPS-induced TNF-alpha plasma levels both alone and in combination with AM404. In contrast, AM404 inhibited LPS-induced increases in circulating interleukin-1beta (IL-1beta) and IL-6. AM251 attenuated the immunosuppressive effect of AM404 on IL-1beta. None of the antagonists altered the effect of AM404 on LPS-induced IL-6. Moreover, AM251, AM630 and SB366791, administered alone, inhibited LPS-induced increases in plasma IL-1beta and IL-6 levels. In conclusion, inhibition of endocannabinoid degradation or transport in vivo potentiates LPS-induced increases in circulating TNF-alpha levels, an effect which may be mediated by PPARgamma and is also reduced by pharmacological blockade of CB1, CB2 and TRPV1. The immunosuppressive effect of AM404 on IL-1beta levels is mediated by the cannabinoid CB1 receptor. Improved understanding of endocannabinoid-mediated regulation of immune function has fundamental physiological and potential therapeutic significance.     

Variations in serum levels of interleukin (IL)-1beta, IL-2, IL-6, and tumor necrosis factor-alpha during specific immunotherapy.

BACKGROUND: Cytokine production by T helper cells is essential for the induction and maintenance of allergic inflammation in the bronchial mucosa. According to recent views, specific immunotherapy (SIT) favors the differentiation of T lymphocytes into cells of the Th1 rather than those of the Th2 subset. OBJECTIVE: To determine whether or not SIT induces a decrease in the inflammatory reaction by studying eventual variations in the serum levels of IL-1beta, IL-2, IL-6, and TNF-alpha in allergic subjects during SIT. METHODS: Serum levels of IL-1beta, IL-2, IL-6, and TNF-alpha were determined before and after 3, 6, and 9 months of SIT by an immunoradiometric assay (IRMA) in 11 adults with perennial allergic asthma and/or rhinitis caused by house dust mites and in 6 nonatopic healthy volunteers. RESULTS: Median serum IL-1beta and TNF-alpha levels of the patients were significantly higher at baseline than those of the controls and decreased during SIT to values similar to or lower (P < .01) after 6 months of SIT for TNF-alpha than those of the controls. Median serum IL-2, significantly lower at baseline than in the controls, increased during SIT to a level similar to that of the controls. Although the median values of IL-1beta and TNF-alpha in the patients tended to decrease and those of IL-2 to increase during SIT, the differences were not significant; the correlation coefficients (r) of the serum levels of IL-1beta IL-6, and TNF-alpha versus duration of SIT were negative, while that of IL-2 was positive. CONCLUSIONS: Decreases in median serum IL-1beta and TNF-alpha levels during SIT, together with the increases in serum IL-2 and IL-6, compared with those of the controls furnish evidence supporting a reduction in the inflammatory response in the course of SIT.     

Cytokines in patients with lung cancer

Lung cancer is one of the most common malignant diseases and is amongst the leading causes of death. Cell-mediated immune response and cytokines could play an important role in antitumour immunity. The aim of the study was to evaluate the cytokines', tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6, releasing capacity in patients with lung carcinoma and benign lung disease. A group of 41 patients were tested for the production of TNF-alpha, IL-1beta and IL-6 in bronchoalveolar lavage (BAL) and blood. The levels of cytokines in the lung cancer patients were: (1) in BAL - IL-6, 173 +/- 85 pg/ml; TNF-alpha, 170 +/- 116 pg/ml; and IL-1beta, 473 +/- 440 pg/ml; (2) in the blood - IL-6, 197 +/- 53 pg/ml; TNF-alpha, 311 +/- 202 pg/ml; and IL-1beta, 915 +/- 239 pg/ml. Alveolar macrophages of the patients with a lung cancer secreted significantly more cytokines, IL-6 (P = 0.0004) and IL-1beta (P = 0.0047), than alveolar macrophages of the patients with a nonmalignant lung cancer. However, significantly lower levels of cytokine production by the BAL cells were found in patients with small cell lung cancer. This production decreased further in phase IV of nonsmall cell lung cancer.     

Soluble antigens from group B streptococci induce cytokine production in human blood cultures.

Group B streptococcal antigens stimulated tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 production in human blood cultures in a concentration- and time-dependent fashion. The minimal concentrations of type-specific polysaccharides, lipoteichoic acid, and group-specific polysaccharide required to produce these effects were, respectively, 0.01, 1, and 10 microg/ml. Cell separation experiments indicated that monocytes were the cell type mainly responsible for cytokine production. Time course studies indicated that TNF-alpha was released before the other cytokines. TNF-alpha, however, did not appear to directly induce IL-1beta, as shown by blockade experiments with anti-TNF-alpha antibodies. IL-6 levels were moderately but significantly decreased by anti-TNF-alpha. These data indicate that several products from group B streptococci are able to directly stimulate human monocytes to release TNF-alpha, IL-1beta, and IL-6. These findings may be clinically relevant, since proinflammatory cytokines can mediate pathophysiologic changes during sepsis.     

Injection of T-cell receptor peptide reduces immunosenescence in aged C57BL/6 mice.

Previous studies established that retrovirally infected young mice produced large amounts of autoantibodies to certain T-cell receptor (TCR) peptides whose administration diminished retrovirus-induced immune abnormalities. C57BL/6 young (4 weeks) and old (16 months) female mice were injected with these same synthetic human TCR V beta 8.1 or 5.2 peptides. Administration of these autoantigenic peptides to old mice prevent immunosenescence, such as age-related reduction in splenocyte proliferation and interleukin-2 (IL-2) secretion. TCR V beta peptide injection into young mice had no effect on T- or B-cell mitogenesis and IL-4 production while modifying tumour necrosis factor-alpha (TNF-alpha), IL-6, and interferon-gamma (IFN-gamma) secreted by mitogen-stimulated spleen cells. TCR V beta injection also retarded the excessive production of IL-4, IL-6 and TNF-alpha induced by ageing. These data suggest that immune dysfunction and abnormal cytokine production, induced by the ageing process, were largely prevented by injection of selected TCR V beta CDR1 peptides.     

Gonadotropin treatment restores in vitro interleukin-1beta and tumour necrosis factor-alpha production by stimulated peripheral blood mononuclear cells from patients with idiopathic hypogonadotropic hypogonadism

In the present study, we aimed to investigate the effects of testosterone deficiency and gonadotropin therapy on the in vitro production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) by peripheral blood mononuclear cells (PBMCs) from patients with idiopathic hypogonadotropic hypogonadism (IHH) in order to elucidate the modulatory role of androgen in cytokine production. Fifteen male patients with untreated IHH and 15 age-matched healthy male subjects were enrolled in the study. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (FT), sex hormone binding globulin (SHBG), prolactin, and IL-2 and IL-4 levels were also measured. In unstimulated cultures, IL-1beta and TNF-alpha secretion were not significantly different between patient and control groups. However, after stimulation with lipopolysaccharide (LPS), secretion of IL-1beta and TNF-alpha was significantly higher in cultures from untreated patients with IHH than in control subjects. Mean FSH, LH and FT levels were significantly lower, whereas SHBG, IL-2 and IL-4 levels were significantly higher in patients with IHH compared than in controls. In patients with IHH, FT negatively affected the serum levels of IL-4 and in vitro secretion of IL-1beta and TNF-alpha. In addition, IL-2 and IL-4 affected the in vitro secretion of IL-1beta in a positive manner. Gonadotropin therapy decreased both TNF-alpha and IL-1beta in PBMCs from patients with IHH. The levels of serum IL-2 and IL-4 were also decreased by therapy. In conclusion, in the present study, gonadotropin treatment restored the in vitro production of IL-1beta and TNF-alpha by PBMCs from patients with IHH, suggesting that androgen modulates proinflammatory cytokine production, at least directly through its effects on PBMCs. It seems probable that this effect plays an important role in the immunosuppressive action of androgens.     

Systemic macrophage activation in locally-induced experimental arthritis

Local and systemic macrophage activation was examined during the course of monoarticular murine antigen-induced arthritis (AIA), induced by systemic immunization and subsequent local induction. The levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-12p70, and nitric oxide (NO) were determined in joints, sera, and supernatants of peritoneal macrophages (the latter unstimulated or stimulated ex vivo with LPS/IFN-gamma). In comparison with normal mice, systemic immunization (day 0) was associated to significant rise of TNF-alpha in serum, IL-1beta in the joints, IL-6 in unstimulated macrophages and IL-12p70 in stimulated macrophages. Local induction led to a further significant increase of: (i) TNF-alpha, IL-1beta, and IL-6 in the joints; and (ii) IL-1beta, and IL-6 in sera and stimulated macrophages during acute and/or early chronic AIA (days 1 to 7). Unstimulated macrophages showed increased NO release (day 3), while stimulated macrophages significantly increased secretion of IL-12p70 (day 1). In late chronic AIA (day 21), cytokine/NO expression returned to immunization levels or below at all sites; solely IL-1beta in the joints remained significantly above normal levels. Therefore, the prevalently local AIA model is characterized by a mixture of local and systemic activation of the mononuclear phagocyte system (MPS). While systemic MPS activation preceding arthritis induction can be attributed to systemic immunization, further systemic activation during arthritis appears an integral pathogenetic component of AIA.     

Early increase in mRNA levels of pro-inflammatory cytokines and their interactions in the mouse hippocampus after transient global ischemia

There is convincing evidence that cytokines are involved in the inflammatory response following cerebral ischemia, but the interactions among the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in the early stage of ischemic reperfusion are not yet completely understood. In this study, we examined the early mRNA expressions of pro-inflammatory cytokines in the ischemic hippocampus after 30 min of bilateral common carotid artery occlusion in C57BL/6J wild-type (WT) and TNF-alpha, IL-1alpha/beta or IL-6 gene knockout (KO) mice utilizing real-time polymerase chain reaction. The mRNA expressions of the pro-inflammatory cytokines TNF-alpha, IL-6 and IL-1beta were significantly induced in ischemic WT mice compared with in the sham-operated mice. These increases peaked at 3 to 24 h for TNF-alpha, at 12 h for IL-1beta, and at 6 to 24 h for IL-6 after ischemia. The pattern of temporal expression of the cytokine mRNAs in ischemic gene KO mice, however, differed from that in WT mice. The TNF-alpha mRNA expression showed a similar temporal expression pattern in IL-6 KO mice compared to in WT mice following ischemic reperfusion, and the levels at all time points were lower than in WT mice. The IL-1beta mRNA level was very low in ischemic TNF-alpha KO mice and IL-6 KO mice in spite of a small peak observed in both at 24 h. The IL-6 mRNA level was significantly upregulated at all time points in both ischemic WT and TNF-alpha KO mice; however, the peak was delayed by 12-h in IL-1alpha/beta KO mice. In conclusion, the present study indicates that the rapid increases in cytokine levels are interdependent, interactive, and possibly modulate each other in the mouse hippocampus after transient global ischemia.     

Multiformic modulation of endotoxin effects by linomide

Linomide is a potent immunomodulator that either enhances or suppresses certain immunological processes. Of particular interest is this compound's capacity to inhibit a variety of organ-specific autoimmune diseases. Here, we report on the effects of linomide on several immunological reactions elicited by endotoxin (LPS), both in vivo and in vitro. In rats and mice linomide inhibited the elicitation of endotoxin-induced uveitis (EIU), an acute inflammatory eye disease that develops within 24 h following footpad injection of LPS. Linomide also inhibited the production of TNF-alpha and IL-6 by LPS-stimulated rat and mouse macrophage monolayers. On the other hand, treatment with linomide significantly increased the levels of IL-1beta (mice and less in rats), IL-6 (rats), and TNF-alpha (mice) in serum samples collected 2 h following injection with LPS. The increased production of proinflammatory cytokines in linomide-treated mice was also indicated by the enhanced lethal effect of LPS in these mice. The finding of elevated levels of these cytokines in animals with suppressed EIU is also in line with previous observations of an inverse relationship between EIU severity and levels of TNF-alpha. Data recorded here underscore the unique capacity of linomide to both enhance and suppress the immune system.     

The effects of alendronate and calcitonin on cytokines in postmenopausal osteoporosis: a 6-month randomized and controlled study

The present study was designed to determine if levels of serum cytokines, such as interleukin (IL)-1beta, IL-2, IL-2r, IL-6, IL-6r, IL-8, IL-10, and TNF-alpha are different in osteoporotic and non-osteoporotic postmenopausal women, and to evaluate the effects of calcitonin and alendronate therapies over a six month period on serum cytokine levels in postmenopausal osteoporotic women. Serum levels of IL-2, TNF-alpha and IL-8 were found to be significantly higher (p < 0.05), and serum IL-10, and IL-6r significantly lower in the calcitonin (N=60) and the alendronate (N=60) treatment groups than in the control group (N=50) (p < 0.05). But, no significant difference was apparent between the calcitonin and alendronate treated groups before treatment. Statistically significant changes occurred in patients, with respect to the levels of serum IL-6r, and IL-8 after one month (p < 0.05), in IL-2r, IL-6r, IL-8, IL-10 after three months, and in IL-1beta, IL-6r, IL-8, IL-10 and TNF-alpha after six months of calcitonin therapy (p < 0.05). No significant difference was observed in IL-6r after one month, in IL-8 and IL-10 after three months, and in TNF-alpha after six months in the calcitonin treated group and in the control group, whereas these parameters were significantly different at baseline. In the alendronate treated group, statistically significant changes occurred in the levels of serum IL-1alpha and IL-6 after three months, and in IL-1beta, IL-6, IL-6r and TNF-alpha after six months (p < 0.05). No significant difference was observed in IL-6r after one month, in IL-10 after three months or in TNF-alpha after six months between the alendronate treatment group and the control group, whereas these parameters were significantly different at baseline. In conclusion, we suggest that; 1) not only IL-1, IL-6, TNF-alpha and IL-11 but also IL-2, IL-8 and IL-10 may have roles in the etiopathogenesis of osteoporosis, 2) calcitonin therapy have a more distinct influence on serum levels of some cytokines and have an earlier effect than alendronate therapy (especially upon IL-2r, IL-8, and IL-10). Nevertheless, further longitudinal studies are needed to identify the cytokines involved in the pathogenesis of postmenopausal osteoporosis and to evaluate the influence of different treatments on these cytokines.