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Objectives: Investigate the presence of a correlation between systemic inflammatory profile of community-dwelling individuals and the loss of muscular mass and performance in old age over a 4.5y follow-up, focusing on the role of anti-inflammatory cytokines in muscular changes in elderly., Design: Longitudinal clinical study., Setting: Subjects were randomly selected from lists of 11 general practitioners in the city of Verona, Italy., Participants: The study included 120 subjects, 92 women and 28 men aged 72.27±2.06 years and with BMI of 26.52±4.07 kg/m2 at baseline., Measurements: Six minutes walking test (6MWT), appendicular and leg fat free mass (FFM) as measured with Dual Energy X-ray absorptiometry, were obtained at baseline and after 4.5 years (4.5y) of mean follow-up. Height, weight, body mass index (BMI), and circulating levels of TNFα, IL-4, IL-10, and IL-13 were evaluated at baseline., Results: A significant reduction of appendicular FFM, leg FFM and 6MWT performance (all p<0.001) was observed after 4.5 y follow-up. In a stepwise regression model, considering appendicular FFM decline as dependent variable, lnIL-4, BMI, baseline appendicular FFM, lnTNFα and lnIL-13 were significant predictors of appendicular FFM decline explaining 30.8% of the variance. While building a stepwise multiple regression considering leg FFM as a dependent variable, lnIL-4, BMI and leg FFM were significant predictors of leg FFM decline and explained 27.4% of variance. When considering 6MWT decline as a dependent variable, baseline 6MWT, lnIL-13 and lnTNFα were significant predictors of 6MWT decline to explain 22.9% of variance., Conclusions: Our study suggest that higher serum levels of anti-inflammatory markers, and in particular IL-4 and IL-13, may play a protective role on FFM and performance maintenance in elderly subjects., Competing Interests: None of the authors have any conflict of interest to disclose.

Zinc (Zn) and selenium (Se) exert regulatory activities on immune functions, while cadmium (Cd) is an immunotoxic agent. The object of this study was to detect effects of 10(-4), 10(-5), and 10(-6) M Cd sulphate, Zn sulphate, and sodium selenite, and their combinations on human peripheral blood mononuclear cell (PBMC) proliferation and IFN-gamma and TNF-alpha production. Only 10(-5) M Zn sulphate significantly enhanced spontaneous PBMC proliferation, which was unaffected by the other salts. At 10(-4) and 10(-5) M, Cd sulphate exerted a dose-response inhibitory action on phytohemagglutinin- (PHA-) stimulated PBMC proliferation and cytokine release, while 10(-4) M and 10(-5) M Zn sulphate and 10(-5) M sodium selenite induced a stimulatory effect on both proliferation and cytokine release; 10(-4) M sodium selenite enhanced only the PBMC proliferation; at 10(-6) M, none of the salts changed the PHA-stimulated immune activity. Moreover, 10(-4) and 10(-5) M Zn and 10(-5) M Se strongly upregulated IFN-gamma (a Th1 cytokine) release, even in presence of 10(-5) M Cd, and reduced the inhibitory effects of Cd on PBMC proliferation and TNF-alpha release. This study confirms that Zn and Se both strongly enhance cytokine release induced by mitogenic stimulation, showing also that Zn acts with a broader range of concentrations than Se. This suggests that dietary excess of Se may not have beneficial effects.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive collagen deposition in the skin and internal organs. Several cytokines and chemokines have been implicated in the induction of fibrosis, but a definitive relationship between specific cytokines and organ involvement has not been established yet. Serum samples, PBMC and T cell lines (TCL) obtained from 54 patients affected by SSc and 20 healthy donors (HD) were examined by ELISA for Interferon-gamma (IFN-gamma ), interleukin (IL)-4, IL-6, IL-10, IL-18, Transforming growth factor (TGF)-beta1, Tumour necrosis factor (TNF)-alpha, sCD30, Macrophage derived chemokine (MDC), Monocyte chemoattractant protein (MCP)-1, Macrophage inflammatory protein (MIP)-1alpha and Regulated on activation normal T-cell expressed and secreted (RANTES). In all the SSc serum samples, we found significantly increased levels of IL6, TNFalpha and MCP-1 but reduced amounts of gamma-IFN and MDC. IL6, IL10, IL18, MIP-1alpha and TNFalpha measured in supernatants from PHA-stimulated PBMC and IL6, MCP-1 and RANTES in supernatants from stimulated TCL were also increased in patients. MDC was decreased in all the biological SSc sources studied. TGF-beta1, IL10, and sCD30 were produced at a significantly lower level by SSc TCL. Serum IL6 and sCD30 levels were significantly increased in dc-SSc patients compared to lc-SSc as were levels of MCP-1 produced by PBMC and IL10 from TCL. We observed a strict relationship between pulmonary fibrosis and IL10, MCP-1 (both from TCL) and serum IL6. Kidney involvement was related to serum MCP-1 levels and IL18 production from PBMC. Oesophageal involvement correlated with MDC production from PBMC and IL10 synthesis by TCL. We showed that IL-6, IL-10, MDC and MCP-1 are variably associated with internal organ involvement and allow the discrimination between limited and diffuse forms of the disease.

The effects of graded concentrations of Pt, Pd, and Rh salts on spontaneous and PHA-stimulated peripheral blood mononuclear cell (PBMC) proliferation and IFN-gamma, TNF-alpha, and IL-5 release were the focus of this study. Spontaneous PBMC proliferation was inhibited by all 10(-4) M salts (with the exception of PtCl2), while it was enhanced by 10(-5) M PtCl2 as well as by 10(-5) and 10(-6) M (NH4)2[RhCl6] and RhCl3 (but not by 10(-7) M salts). Pt, Pd, and Rh compounds showed similar effects on PHA-stimulated PBMC proliferation and cytokine release; however, the effects on IFN-gamma release were stronger. Thus, 10(-4) and 10(-5) M (NH4)2[PtCl6] and 10(-4) M (NH4)2[PtCl4] inhibited the PHA-stimulated immune activity; 10(-4) M PtCl2 did not exert activity, while 10(-6) M (NH4)2[PtCl6] and 10(-5) and 10(-6) M (NH4)2[PtCl4] and PtCl2 enhanced PBMC proliferation and/or cytokine release. (NH4)2[PdCl6] showed stronger dose-related inhibitory effects (present also at 10(-7) M concentration) on PHA-stimulated proliferation and cytokine release than (NH4)2[PdCl4], PdCl2, or Rh salts; the inhibitory activity of (NH4)2[RhCl6] was slightly higher than that of RhCl3. In conclusion, this study shows that: (a) the immune capacity of Pt, Pd, and Rh depends on speciation; (b) low concentrations of Pt salts stimulate spontaneous and PHA-stimulated immune responses; (c) the in vitro activity of Pd compounds (which are only inhibitory) is higher than that of Pt and Rh salts. These findings are consistent with the observations that sensitization and allergic contact dermatitis in response to Pd are increased in the general population, although the roles of cross-sensitization to Pd and Ni are difficult to determine.

In vitro immune effects of Pt compounds of occupational and/or environmental importance, or those used in cancer treatment were studied. Spontaneous and PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) and in vitro release of TNF-alpha, IFN-gamma, and IL-5 were assessed in presence of high and very low concentrations of Pt salts: 10(-4) and 10(-7) M (NH4)2[PtCl6], (NH4)2[PtCl4], PtCl4, PtCl2, Na2PtI6, and cis-diaminedichloroPt (CisPt). Spontaneous and PHA-stimulated PBMC proliferation were both inhibited by 10(-4) M (NH4)2[PtCl6] and (NH4)2[PtCl4], while only PHA-stimulated proliferation was inhibited by 10(-4) M CisPt, without significant effects of the other Pt salts. TNF-alpha release from PBMC was reduced by 10(-4) M (NH4)2[PtCl6] and INF-gamma release was reduced by 10(-4) and 10(-7) M hexa- and tetrachloroplatinate and 10(-4) M Na2PtI6, but not by other Pt salts. IL-5 release (related to the Th2 immune response) was inhibited by 10(-4) M (NH4)2[PtCl6], (NH4)2[PtCl4] and Na2PtI6, but it was enhanced by both 10(-4) and 10(-7) M PtCl4. PtCl2 did not influence the immune effects. The study shows Pt salts have immune effects and their potency is ranked in the following order: (NH4)2[PtCl6] > (NH4)2[PtCl4] > Na2PtI6 and CisPt > PtCl4 > PtCl2. These results indicate that certain Pt salts affect lymphocyte proliferation and cytokine release. The intracellular mechanisms responsible for such effects have not been identified.

Proinflammatory cytokines are deemed to play a pivotal role in the pathogenesis of multiple sderosis (MS). They provide signals for T-cell activation and inflammatory cell recruitment in the brain and might directly alter neuroglial and neuronal cell survival and function. We found that peripheral blood mononuclear cells (PBMCs) from MS patents spontaneously produce high levels of TNFalpha, TNFbeta, IFNgamma, and oncostatin M (oncM), a proinflammatory cytokine actng on cells of neural, vascular, hematopoietic, and lymphoid origin. Spontaneous production of these cytokines was significantly higher (p < 0.01) in PBMC short-term culture supernatants from MS patients than in blood donors (HC). On average, lectin-induced production of these cytokines by PBMC was higher in MS patents than in HC significantly so only for TNFalpha (p = 0.013). Determination of TNFalpha, TNFbeta IFNgamma, and oncM in corresponding sera showed that on average, oncM levels were higher in MS patients than in HC, though the results were not statistically significant whereas levels of TNFalpha, TNFbeta and IFNgamma were below the assay threshold in most patients. The finding that MS PBMCs are primed in vivo to produce and release high levels of proinflammatory cytokines suggests the presence of a basal activation of the immune system which, in turn, may play a role in the complex circuitry of molecular and cellular interactions responsible for neurologic damage in MS.

In vitro hemopoiesis and hemopoietic cytokines production were evaluated in 9 centenarians (median age 100.5 years, age range: 100-104 years), 10 old people (median age: 71 years, age range: 66-73 years), and 10 young people (median age: 35 years, age range: 30-45 years), all carefully selected for their healthy status. The main findings were the following: (i) a trend towards a decreased absolute number of CD34+ progenitor cells in the peripheral blood of old people and centenarians, in comparison to young subjects; (ii) a well-preserved capability of CD34+ cells from old people and centenarians to respond to hemopoietic cytokines, and to form erythroid (BFU-E), granulocyte-macrophagic (CFU-GM), and mixed colonies (CFU-GEMM) in a way (number, size, and morphology) indistinguishable from that of young subjects; (iii) an age-related decreased in vitro production of granulocyte-macrophagic colony-stimulating factor (GM-CSF) and a decreased production of interleukin-3 (IL-3) in centenarians by phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC); (iv) a linear increase of the serum level of stem cell factor (SCF), measured in the above-mentioned subjects and in 65 additional subjects, including 4 centenarians. These data suggest that basal hematopoietic potential is well preserved in healthy centenarians, and that the hemopoietic cytokine network undergoes a complex remodeling with age.

The interactions between B and T lymphocytes, leading to the development of humoral responses, are reviewed with references to the changes occurring in aged people. Aging is perceived as a process of impairment of immune functions; it is known that T cells from aged subjects have a reduced ability to produce IL-2. However, other functions seem to be upregulated in elderly subjects; indeed, IL-1, IL-3, IL-4, IL-6 and TNF alpha production are increased both in aged mice and humans. These cytokines are known to control B cell differentiation, through isotype switch and Ig production. A significant increase in IgG subclasses and IgA is observed in sera of aged subjects. This contrasts with the significant decrease in circulating B lymphocytes. The impairment of primary responses to immunization, and other aspects of humoral immunity, including mucosal responses, autoantibody production and correlations with phenotypic markers of T and B cell subsets, are discussed.

The production of cytokines during aging, except interleukin (IL)-2, has been neglected in humans. We measured the in vitro production of IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and IL-1 beta by peripheral mononuclear cells from selected healthy young (mean age 26.8 years) and aged (mean age 80.2 years) subjects. Significant increases of IL-6, TNF-alpha and IL-1 beta levels were found in mitogen-stimulated cultures from aged donors, occurring at 24 to 72 h after stimulation. No significant differences were observed for IFN-gamma production. Proliferative capability of cells stimulated with PHA was not impaired in aged subjects. Since the amounts of all cytokines studied were similar in unstimulated cultures from young and aged subjects, and also serum levels of TNF-alpha did not differ, these data indicate that the cellular machinery for the production of these cytokines is well preserved in aging, and also that cells from old people are able to up-regulate their production in response to appropriate stimuli. The increases in cytokine synthesis were not dependent on changes in the number of monocytes, nor were they related to the significant rise of CD45RO+, and the concomitant decrease of CD45RA+, occurring in both CD4+ and CD8+ lymphocytes from aged subjects. The increased production of pro-inflammatory cytokines by stimulated mononuclear cells of healthy aged subjects may be relevant to several aspects of age-associated pathological events, including atherosclerosis, osteoporosis, fibrosis and dementia.

Proinflammatory cytokines are deemed to play a pivotal role in the pathogenesis of multiple sclerosis (MS). They provide signals for T-cell activation and inflammatory cell recruitment in the brain and might directly alter neuroglial and neuronal cell survival and function. We found that peripheral blood mononuclear cells (PBMCs) from MS patients spontaneously produce high levels of TNFα , TNFβ , IFNγ, and oncostatin M (oncM), a proinflammatory cytokine acting on cells of neural, vascular, hematopoietic, and lymphoid origin. Spontaneous production of these cytokines was significantly higher (p<0.01) in PBMC short-term culture supernatants from MS patients than in blood donors (HC). On average, lectin-induced production of these cytokines by PBMC was higher in MS patients than in HC, significantly so only for TNFα (p=0.013). Determination of TNFα, TNFβ, IFNγ, and oncM in corresponding sera showed that, on average, oncM levels were higher in MS patients than in HC, though the results were not statistically significant, whereas levels of TNFα, TNFβ, and IFNγ were below the assay threshold in most patients. The finding that MS PBMCs are primed in vivo to produce and release high levels of proinflammatory cytokines suggests the presence of a basal activation of the immune system which, in turn, may play a role in the complex circuitry of molecular and cellular interactions responsible for neurologic damage in MS. [ABSTRACT FROM AUTHOR]

Investigates the resistance of type-2 cytokine T cells to apoptosis. Increase in Bcl-2 expression in type-2 cells; Functional classification of T lymphocytes; Implication of type-1 and -2 T cells for neonatal tolerance.

The definition of probiotics is always evolving, since it includes natural live micro-organisms, cellular subfractions, as well as genetically engineered derivatives or proteins. The scope of probiotic administration is a beneficial change of the intestinal microflora, and improvement of nonimmune or immune resistance in the intestinal tract. Very few controlled human studies have been reported, but many in vitro and experimental animal studies point to their safety and potentially useful applications. We shall review the published reports and discuss mainly the prospective uses in the field of allergic diseases, with reference to the implication of the natural (innate) immune system as regulator of the development of abnormal responses to ingested food antigens. [ABSTRACT FROM AUTHOR]