Aged humans and rodents are susceptible to infection with Streptococcus pneumoniae bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines and increased production of interleukin (IL)-10 by macrophages (Mphi) from aged mice. To understand the molecular basis of cytokine dysregulation in aged mouse Mphi, a microarray analysis was performed on RNA from resting and lipopolysaccharide (LPS)-stimulated Mphi from aged and control mice using the Affymetrix Mouse Genome 430 2.0 gene chip. Two-way ANOVA analysis demonstrated that at an overall P < 0.01 level, 853 genes were regulated by LPS (169 in only the young, 184 in only the aged, and 500 in both). Expression analysis of systematic explorer revealed that immune response (proinflammatory chemokines, cytokines, and their receptors) and signal transduction genes were specifically reduced in aged mouse Mphi. Accordingly, expression of Il1 and Il6 was reduced, and Il10 was increased, confirming our previous results. There was also decreased expression of interferon-gamma. Genes in the Toll-like receptor-signaling pathway leading to nuclear factor-kappaB activation were also down-regulated but IL-1 receptor-associated kinase 3, a negative regulator of this pathway, was increased in aged mice. An increase in expression of the gene for p38 mitogen-activated protein kinase (MAPK) was observed with a corresponding increase in protein expression and enzyme activity confirmed by Western blotting. Low doses of a p38 MAPK inhibitor (SB203580) enhanced proinflammatory cytokine production by Mphi and reduced IL-10 levels, indicating that increased p38 MAPK activity has a role in cytokine dysregulation in the aged mouse Mphi.
Neonatal humans and rodents are susceptible to infection with encapsulated bacteria as a result of an inability to make antibodies to capsular polysaccharides. This is partly a result of decreased production of proinflammatory cytokines by splenic macrophages (MPhi) from neonates. In this study, we show that when stimulated with a variety of agonists to TLR2, -4, and -9, neonatal MPhi make less proinflammatory cytokines and more IL-10 than adult MPhi. IL-10 appears to have a role in the decreased proinflammatory cytokine production, as neonatal MPhi treated with anti-IL-10 receptor antibody or from IL-10(-/-) mice produced levels of proinflammatory cytokines at a level comparable with that produced by adult MPhi. A microarray analysis of RNA from resting and LPS-stimulated MPhi from neonatal and adult mice showed that expression of a large number of genes encoding cytokines, chemokines, and their receptors was decreased dramatically in the neonatal MPhi, although some cytokines, including IL-10 and IL-16, were enhanced. Several genes in the TLR signaling pathway leading to NF-kappaB activation were down-regulated, which may account for the decreased chemokine and cytokine synthesis. It is surprising that p38alpha MAPK, known to be required for TLR-induced cytokine secretion, was enhanced in the neonatal MPhi. Our studies with the p38 MAPK inhibitor SB203580 suggested that excess p38 MAPK activity can be inhibitory for TLR2-, -4-, and -9-induced production of proinflammatory cytokines but not IL-10. The anti-inflammatory phenotype of the neonatal Mphi may be unique to the developing organism, although it compromises the neonate's ability to respond to encapsulated bacteria.
Aim: Clinical and biological studies in the past years underlined the proinflammatory action of the citokine Tumoral Necrosis Factor in the pathophysiolology of psoriasis, psoriatic arthritis, rheumatoid arthritis. Knowing that the high dilution of substances can have an inverted effect, our hypotesis was that dillution made of TNF-alfa can decrease the clinical manifestation of such diseases. Materials and method: We included as a pilot group 10 patients presented in Lotus Life Integrative Medicine Center or Profamilia Medical Center Iasi with psoriasis and rheumatoid arthritis previously diagnosed by specialists, under speciality treatment with insufficient results and patients who deliberately expressed their preference for alternative treatment. We decided to exclude the patients which during the study could present aggravation of symptoms. The treatment protocol consisted in the administration under the tongue of the dilution of TNF-alfa 9CH in liquid form, 12 drops twice a day for at least 3 months. This was prepared diluting from Guna TNF-alfa 4CH in distiled water, completing with 30% of alcohol in the last solution. Patients under other medications continued to take their previous treatment unchanged. We called the patients for follow-up after 3 months. We took the written consent from the patients and the approval of the Ethical Committee of the University of Medicine and Pharmacy "Gr. T. Popa" of Iasi. Results: To analize the results we followed the subjective evolution of the patients, the total surface and thickness of eruptions in psoriasis patients and the pain intensity and stiffness in arthritis patients. Under this conditions, all the patients showed amelioration, with 2 out of 6 psoriasis patients showing complete clearance of eruptions. No patient reported adverse reactions during the treatment Conclusions: Even though the group of patients was small and not appropriate for statistical data the presence of a clinical response in all the patients and the absence of adverse reactions sustains the opportunity to extend the research on this subject.
Due to the inability of the immune systems of aged and neonatal humans and rodents to make sufficient Ab to the capsular polysaccharides (PS), they are susceptible to infections by PS encapsulated bacteria. This lack of anti‐PS Ab is due to MΦ not being able to produce B cell stimulatory cytokines. When stimulated by TLR agonists, murine neonatal and aged MΦ make less pro‐inflammatory cytokines (p‐ic) and more IL‐10 than adult MΦ. Neutralization of IL‐10 allowed them to produce levels of p‐ic comparable to that produced by young adult MΦ. A microarray analysis was performed on RNA from resting and TLR‐4‐stimulated murine splenic MΦ. Expression of genes encoding the TLR signaling pathway, cytokines, chemokines, and their receptors was decreased in neonatal and aged MΦ, but p38 MAPK was enhanced in neonatal and aged MΦ. Surprisingly p38 had a dual role in p‐ic production with excess p38 levels being inhibitory. Suboptimal levels of p38 inhibitor enhanced p‐ic production but inhibited IL‐10 production. In vivo, a partial inhibition of p38 also suppressed TLR‐4 induced IL‐10 production without affecting p‐ic production. A partial inhibition of p38, considerably enhanced production of PS specific Ab in aged mice. TLR‐4 induced IL‐10 production was similarly dependent on p38 in human cord blood monocytes. Thus, elevated p38 activity in aged and neonatal MΦ leads to diminished help for B cells to mount an Ab response against PS.
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