Increased expression of pro-inflammatory cytokines in placentas of women undergoing spontaneous preterm delivery or premature rupture of membranes

PROBLEM: The objective of this study was to determine the levels of cytokines in the placentas of women undergoing preterm delivery (PTD) or premature rupture of membranes (PROM) as compared with women undergoing normal delivery at term. METHOD OF STUDY: Placentas were obtained from 30 subjects with spontaneous PTD, 30 women with PROM and 30 women with a history of normal delivery at term. Levels of interleukin (IL)-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, TNF-beta, IL-4, IL-5, IL-6 and IL-10 and IL-12 were estimated by ELISA in detergent lysates of placentas from the subjects. RESULTS: We found significantly increased levels of the Th1 cytokines IL-2 and IFN gamma and of the Th1-inducing cytokine IL-12 in placentas from the PTD and PROM groups as compared with those delivering at term. In contrast, the levels of the Th2 cytokines IL-4, IL-6 and IL-10 were significantly higher in placentas from term pregnancy. CONCLUSIONS: These data support our observation of a pro-inflammatory cytokine bias in women with PTD and PROM.     

Pro-inflammatory maternal cytokine profile in preterm delivery

PROBLEM: The objective of this study was to determine the levels of cytokines produced by maternal peripheral blood mononuclear cells (PBMC) upon stimulation with a mitogen, with autologous placental cells and with a trophoblast antigen extract. METHOD OF STUDY: Peripheral blood mononuclear cells from 54 women with a history of successful pregnancy and 30 women undergoing preterm delivery (PTD) were stimulated with the mitogen and antigens, and the cytokine levels in mitogen-stimulated culture supernatants assessed. RESULTS: Significantly higher levels of the type 1 cytokines, interferon (IFN)-gamma and interleukin (IL)-2, were produced by the PTD group than by the normal pregnancy group, which on the contrary showed significantly greater production of the type 2 cytokines, IL-4, IL-5 and IL-10. A comparison of the ratios of type 2 to type 1 cytokines is indicative of a type 1 cytokine bias in PTD. CONCLUSIONS: These data are suggestive of a maternal type 1 cytokine bias in PTD.     

Apoptotic cells selectively suppress the Th1 cytokine interferon γ in stimulated human peripheral blood mononuclear cells and shift the Th1/Th2 balance towards Th2

Apoptotic cells are readily recognized and engulfed by phagocytes and usually do not induce inflammation or tissue damage. Furthermore, they can actively suppress a pro-inflammatory response in phagocytes: In the presence of apoptotic cells, activated monocytes/macrophages produce more of the anti-inflammatory and immunoregulatory cytokines IL-10 and TGF-β, but less of the pro-inflammatory cytokines TNFα, IL-1β and IL-12. This immunoregulatory effect is most likely mediated by several receptors on monocytes/macrophages including the thrombospondin receptor (CD36). In addition to the modulation of cytokine secretion, apoptotic cell material inhibited the expression of MHC class II molecules on the surface of monocytes/macrophages. Decreased MHC II expression appeared to be mediated predominantly by increased IL-10 secretion in a para-/autocrine manner. Here, we show that the functional modulation of antigen-presenting monocytes/macrophages by apoptotic cells also influences T cell activation and function. When human peripheral blood mononuclear cells were stimulated with recall antigens in the presence of apoptotic cells, interferonγ (IFNγ) secretion was markedly suppressed, whereas secretion of the Th2 cytokine IL-4 was not significantly altered. Hence, apoptotic cells shift the T cell cytokine secretion pattern towards a Th2-like response. This Th2 shift can largely be prevented by neutralizing IL-10, indicating an important role of this cytokine for modulating T cell cytokine secretion patterns.     

Apoptotic cells selectively suppress the Th1 cytokine interferon gamma in stimulated human peripheral blood mononuclear cells and shift the Th1/Th2 balance towards Th2

Apoptotic cells are readily recognized and engulfed by phagocytes and usually do not induce inflammation or tissue damage. Furthermore, they can actively suppress a pro-inflammatory response in phagocytes: In the presence of apoptotic cells, activated monocytes/macrophages produce more of the anti-inflammatory and immunoregulatory cytokines IL-10 and TGF-beta, but less of the pro-inflammatory cytokines TNFalpha, IL-1beta and IL-12. This immunoregulatory effect is most likely mediated by several receptors on monocytes/macrophages including the thrombospondin receptor (CD36). In addition to the modulation of cytokine secretion, apoptotic cell material inhibited the expression of MHC class II molecules on the surface of monocytes/macrophages. Decreased MHC II expression appeared to be mediated predominantly by increased IL-10 secretion in a para-/autocrine manner. Here, we show that the functional modulation of antigen-presenting monocytes/macrophages by apoptotic cells also influences T cell activation and function. When human peripheral blood mononuclear cells were stimulated with recall antigens in the presence of apoptotic cells, interferon gamma (IFN gamma) secretion was markedly suppressed, whereas secretion of the Th2 cytokine IL-4 was not significantly altered. Hence, apoptotic cells shift the T cell cytokine secretion pattern towards a Th2-like response. This Th2 shift can largely be prevented by neutralizing IL-10, indicating an important role of this cytokine for modulating T cell cytokine secretion patterns.     

Cytokine Production by Lymphocytes in Pregnancy

PROBLEM: In the presence of progesterone lymphocytes of pregnant women release a 34- kDa protein named the progesterone-induced blocking factor (PIBF). PIBF mediates the immunomodulatory and anti-abortive effects of progesterone and its presence is related to the outcome of pregnancy. PIBF induces production of Th2 type cytokines by activated lymphocytes. The in vivo relationship between PIBF- and cytokine production of pregnancy lymphocytes and the outcome of pregnancy was investigated. METHOD OF STUDY: Interleukin (IL)-12 and IL-10 production and PIBF expression in peripheral lymphocytes of 111 healthy pregnant women and 120 women at risk for premature pregnancy termination were detected by immunocytochemistry. RESULTS: We found increased IL-12 and low PIBF and IL-10 expression on lymphocytes of “risk” patients, and a high rate of IL-10 and PIBF positivity on lymphocytes from healthy pregnant women. The cytokine production pattern of the lymphocytes was related to the presence or absence of previous abortions as well as to the outcome of pregnancy. CONCLUSION: These data suggest the involvement of an altered cytokine production pattern in the immunologic effects of progesterone.     

Aluminium hydroxide down-regulates T helper 2 responses by allergen-stimulated human peripheral blood mononuclear cells

BACKGROUND: Aluminium hydroxide (alum) is a commonly used adjuvant for specific immunotherapy of allergic diseases. While alum is traditionally associated with murine Th2 sensitization, little is known about its effects on secondary allergic responses in humans. METHODS: We investigated the in vitro effects of alum on peripheral blood mononuclear cells (PBMC) from atopic donors. PBMC from 18 grass pollen-sensitive rhinitic subjects were stimulated with Phleum pratense (Phl p) in the presence or absence of alum. After 6 days culture, cytokine production was measured by ELISA and T cell proliferation by radiolabelled thymidine incorporation. The effect of alum on the expression of human leucocyte antigen and CD80/CD86 on cultured antigen-presenting cells was assessed by flow cytometry. RESULTS: PBMC cultured with Phl p and alum showed a significant decrease in both IL-5 and IL-13 production compared with allergen alone (P<0.005 and P<0.001, respectively), but no change in IFN-gamma or IL-12 production or proliferative responses. These alum-induced changes in T helper (Th)2 cytokine production were unaffected by the addition of neutralizing antibodies to IL-4 or IL-12. Culture of PBMC with alum induced increased expression of CD86 (P=0.004) and HLA (P=0.01) on monocytes while the expression of CD80 was decreased (P=0.02). SUMMARY: Alum down-regulates allergen-driven Th2 cytokine responses while Th1 cytokines are unaffected. These data confirm that alum is a useful adjuvant for inclusion in allergen immunotherapy vaccines.     

Ebastine inhibits T cell migration, production of Th2-type cytokines and proinflammatory cytokines

BACKGROUND: Cytokine imbalance and cellular migration to inflammatory sites are critical components of allergic diseases. Redirecting cytokine imbalance and inhibiting cell migration therefore represent important therapeutic strategies for the treatment of these disorders. OBJECTIVES: To study the in vitro effect of ebastine, a novel non-sedating H1 receptor antagonist, on cytokine secretion and migration of activated T cells, as well as production of pro-inflammatory cytokines by macrophages. METHODS: Peripheral T cells obtained from healthy volunteers were cultured in wells coated with the combination of anti-CD3 monoclonal antibody (mAb) and anti-CD26 mAb, anti-CD3 mAb and anti-CD28 mAb, or anti-CD3 mAb with PMA, in the presence or absence of ebastine. T cell proliferation and the production of cytokines were measured by [3H]thymidine incorporation assay and ELISA, respectively. In addition, transendothelial migration of T cells and production of pro-inflammatory cytokines by macrophages were examined. RESULTS: Ebastine inhibited T cell proliferation and the production of IL-4, IL-5, IL-6, and TNF-alpha by T cells under each co-stimulatory condition tested, whereas it exhibited no effect on the production of IL-2 or IFN-gamma. In addition, T cell migration and the production of such pro-inflammatory cytokines as TNF-alpha and IL-6 by macrophages were inhibited by ebastine. CONCLUSIONS: These results indicate that ebastine has a specific inhibitory effect on Th2-type cytokine production. Moreover, ebastine inhibited T cell migration and pro-inflammatory cytokine production by T cells and macrophages, suggesting that ebastine might be useful for the treatment of T cell-mediated allergic inflammatory disorders, including asthma, atopic dermatitis, and Th2-type autoimmune diseases.     

Maternal cytokine production patterns in women with pre-eclampsia

PROBLEM: To determine the levels of cytokines produced upon mitogenic or antigenic stimulation of maternal peripheral blood mononuclear cells (PBMC) from women with pre-eclampsia. METHOD OF STUDY: PBMC from 54 women with a history of successful pregnancy and 32 women undergoing pre-eclamptic delivery were stimulated with a mitogen or with autologous placental cells or with trophoblast antigens, and the levels of cytokines released into the culture supernatants then assessed by enzyme-linked immunosorbent assay. RESULTS: Significantly higher levels of the Th1 cytokines, interferon-gamma, and tumor necrosis factor-alpha were produced by the pre-eclamptic group than by the normal pregnancy group, which on the contrary showed significantly greater production of the Th2 cytokines, interleukin (IL)-4, IL-5, IL-6 and IL-10. A comparison of the ratios of Th2 to Th1 cytokines indicates a higher Th1 cytokine bias in pre-eclampsia as compared with normal pregnancy. CONCLUSIONS: These data are suggestive of a maternal pro-inflammatory cytokine bias in pre-eclampsia.     

Effect of bronchial allergen challenge on in vitro cytokine release by peripheral blood mononuclear cells of atopic patients

Background During the pollen season, peripheral blood mononuclear cells (PBMC) from allergic patients produce increased levels of Th2 cytokines after stimulation with allergen in vitro . We have studied the effect of a single bronchial provocation test (BPT) of allergic patients to determine whether allergen challenge in vivo modulates cytokine production by PBMC, after subsequent stimulation with the same allergen in vitro .
Methods Twelve atopic asthmatic patients were challenged with the relevant allergen, and their PBMC, isolated before (TO) or 6 (T6) or 24 h (T24) after BPT, respectively, were cultured for 120 h in the presence or absence of the same allergen, after which cytokine production was measured by ELISA. Results Allergen-specific activation of the PBMC at TO resulted in interleukin (IL)-5 and IL-13 production, but not in detectable levels of interferon-gamma and IL-4. BPT did not induce the secretion of the latter cytokines. However, IL-5 and lL-13 production was significantly decreased at T24, as compared to TO. No statistically significant differences were found between the production of IL-10 before and after BPT.
Conclusions In contrast to the effects of natural challenge with allergen, a decrease in the production of some Th2 cytokines by peripheral blood T cells was observed 24 h after BPT, suggesting a concomitant decrease in the frequency of allergen-specific T cells in the circulation.     

Regulation of cytokine production in human peripheral blood mononuclear cells and allergen-specific th cell clones by 1alpha,25-dihydroxyvitamin D3

BACKGROUND: The steroid hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol), in addition to its crucial role in calcium homeostasis, exerts several effects on the immune system by regulating cell proliferation, differentiation, and maturation. These effects may be exerted through the control of protooncogenes and the regulation of cytokine production. METHODS: The influence of calcitriol on cytokines secretion by human peripheral blood mononuclear cells (PBMC) isolated from healthy donors, and by allergen-specific T helper (Th) cell clones was studied. PBMC were cultured for 48 h with phorbol myristate acetate (PMA) and ionomycin in the presence or absence of calcitriol. Human Th cell clones were stimulated with either Bet v 1 allergen or anti-CD3 antibodies and PMA. Cytokines were measured in the supernatants by ELISA, and at single-cell level by FACS. RESULTS: Calcitriol significantly inhibited the production of IL-2, IFN-gamma and IL-12 by PBMC, as well as the percentage of CD4+ T cells containing intracytoplasmic IL-2 and IFN-gamma. Interestingly, calcitriol-treated PBMC induced the production of IL-10 and IL-5, but not of IL-4. The effect of calcitriol was maximal at 10(-7) to 10(-9) and noneffective at 10(-11) M. Calcitriol diminished the secretion of IL-1, TNF-alpha, and MG-CSF in PBMC. Furthermore, calcitriol also decreased the secretion of IL-2 and IFN-gamma by Th1 clones, and of IL-4 by Th2 clones. CONCLUSIONS: Our data strongly support the notion that calcitriol modulates the production of cytokines in a time- and concentration-dependent manner, and suggest that nonhypercalcemic derivatives of 1alpha,25-dihydroxyvitamin D(3) may be used for new immunosuppressive therapies.     

Non-LPS components of Chlamydia pneumoniae stimulate cytokine production through Toll-like receptor 2-dependent pathways

Recent studies suggest that infection with Chlamydia pneumoniae is associated with atherosclerosis, and that cytokines play an important role in the initiation and progression of Chlamydia-induced inflammation. When freshly isolated peripheral blood mononuclear cells (PBMC) were stimulated for 24 h with sonicated C. pneumoniae, significant amounts of the pro-inflammatory cytokines TNF-alpha and IL-1beta and of the anti-inflammatory cytokine IL-10 were released into the supernatant. The addition of serum increased cytokine release induced by C. pneumonia two- to fivefold (p < 0.01). This effect was not due to complement, mannose-binding lectin (MBL) or lipopolysaccharide-binding protein (LBP). Incubation of PBMC with either anti-Toll-like receptor 4 (TLR4) or anti-CD14 blocking antibodies did not influence the production of cytokines induced by Chlamydia. The induction of cytokines by C. pneumoniae in macrophages from C3H / HeJ mice, known to have a defective TLR4, was identical to that measured in control macrophages from C3H / HeN mice. In contrast, incubation of PBMC with an anti-TLR2 blocking antibody significantly inhibited the production of TNF by 67 % and of IL-1beta by 72 %. In conclusion, C. pneumoniae stimulates cytokine production in a serum-dependent manner, but independently of complement, MBL and LBP. C. pneumoniae induces the pro-inflammatory cytokines TNF and IL-1beta through TLR2, but not TLR4 and CD14.     

Insulin-like growth factor-I stimulates IL-10 production in human T cells

There is vast body of evidence that the insulin-like growth factor (IGF)-I exerts immunomodulatory effects in vitro and in vivo. In vitro studies indicate that stimulatory effects of IGF-I may be exerted through augmentation of inflammatory cytokine production. To further explore the immunomodulatory effects of IGF-I through regulation of cytokine production, we tested the in vitro effects of IGF-I on the secretion of inflammatory T helper cell type 1 (Th1) and Th2 cytokines by human peripheral blood mononuclear cells (PBMC). To this end, PBMC were stimulated with the T cell mitogen phytohemagglutinin (PHA), and cytokines in the culture media were assessed after 18, 42, 66, and 80 h of culture. We found that IGF-I stimulated the secretion of the Th2 cytokine interleukin (IL)-10 by 40-70% in PHA-stimulated PBMC. In addition, we observed a small stimulatory effect (15%) on the secretion of another Th2 cytokine IL-4. The secretion of IL-2, IL-5, IL-6, interferon-gamma, and the inflammatory cytokines IL-1beta, IL-8, and tumor necrosis factor alpha was not or was hardly affected. IL-10 secretion was also stimulated in purified T cells, and we established that IGF-I also stimulated IL-10 mRNA expression by 100-150%. The monocyte-activating bacterial cell-wall product lipopolysaccharide induced IL-10 production in PBMC, but this was not affected by IGF-I. As IL-10 predominantly exerts anti-inflammatory actions and suppresses Th1-dependent immune responses, our results indicate that IGF-I may exert inhibitory actions on inflammatory and Th1-mediated cellular immune responses through stimulation of IL-10 production in T cells.     

Regulation of immune responses by interleukin-27

Summary: Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including autoimmunity. Recently, interleukin-27 (IL-27) was identified, which, along with IL-12, IL-23, and IL-35, belongs to the IL-12 cytokine family. These family members play roles in the regulation of T helper (Th) cell differentiation. IL-27 is unique in that while it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyper-production of various pro-inflammatory cytokines concomitant with severe inflammation in affected organs was observed in IL-27 receptor α chain (WSX-1)-deficient mice infected with Trypanosoma cruzi. Experimental allergic or inflammatory responses were also enhanced in WSX-1-deficient mice. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th17 cells (a newly identified inflammatory T-helper population) and induction of IL-10 production. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies on the role of IL-27 in immunity to parasitic and bacterial infections as well as in allergy and autoimmunity in view of its pro- and anti-inflammatory properties.     

Nickel-induced IL-10 down-regulates Th1- but not Th2-type cytokine responses to the contact allergen nickel

Whereas the involvement of Th1- and Th2-type cytokines in contact allergy to nickel (Ni) is well documented, the role of the regulatory cytokine IL-10 is less clear. We therefore investigated the impact of IL-10 on Ni-induced Th1- (IFN-gamma) and Th2-type (IL-4 and IL-13) cytokine responses in human peripheral blood mononuclear cells (PBMC). PBMC from 15 blood donors with reactivity to Ni (Ni-PBMC) and 8 control donors devoid of reactivity (control PBMC) were stimulated with Ni and the frequency of cytokine-producing cells and the levels of secreted cytokines were analysed by ELISpot (IL-4, IL-13 and IFN-gamma) and ELISA (IL-10, IL-13 and IFN-gamma), respectively. The Ni-induced response was further assessed in the presence of recombinant IL-10 (rIL-10) or neutralizing antibody to IL-10 and the phenotype of the Ni-specific cytokine-producing cells regulated by IL-10 was determined by cell depletion experiments. Ni induced IL-10 production in Ni-PBMC (mean, (range); 33.1 pg/ml (0-93.4 pg/ml)) but not control PBMC (2.2 pg/ml (0-14.9 pg/ml)) (P = 0.002). Ni also induced significant production of IL-4, IL-13 and IFN-gamma that correlated with the IL-10 response. Addition of rIL-10 down-regulated the Ni-induced production of all cytokines but with a more pronounced effect on IFN-gamma. However, neutralization of Ni-induced IL-10 enhanced the levels of IFN-gamma induced by Ni (P = 0.004) but did not affect the number of IFN-gamma-producing cells or the production of other cytokines. Cell depletion experiments suggested that the Ni-specific IFN-gamma (and Th2-type cytokine) producing cells were CD4(+) T cells. The impact of IL-10 on Ni-induced IFN-gamma responses by CD4(+) T cells suggests that an important role of IL-10 in vivo is to counteract the allergic reactions mediated by Th1-type cytokines.     

Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines

BACKGROUND: Decreased exposure to microbial stimuli has been proposed to be involved in the increased prevalence of atopic disease. Such a relationship was indicated by enhanced presence of typical probiotic bacteria in the intestinal flora correlating with reduced prevalence of atopic disease. Recent clinical trials suggested that probiotic bacteria may decrease and prevent allergic symptoms, but which (different) species or strains may contribute is poorly understood. OBJECTIVE: We sought to select probiotic bacteria by their ability to modulate in vitro production of cytokines by peripheral blood mononuclear cells (PBMCs), to make a rational choice from available strains. METHODS: PBMCs, purified monocytes, and lymphocytes from healthy donors were co-cultured with 13 different strains of probiotic bacteria. The effect of lactic acid bacteria (LAB) on different cell populations and effects on cytokine production induced by the polyclonal T cell stimulator phytohaemagglutinin (PHA) was evaluated by measuring T helper type 1, T helper type 2 (Th2), and regulatory cell cytokines in culture supernatants by multiplex assay. RESULTS: PBMCs cultured with different strains produced large amounts of IL-10 and low levels of IL-12p70, IL-5, and IL-13. In PHA-stimulated PBMC cultures, the tested strains decreased the production of Th2 cytokines. Neutralizing IL-10 production resulted in partial to full restoration of Th2 cytokine production and concurred with an increase in pro-inflammatory cytokines such as IL-12p70 and TNF-alpha. Within the PBMCs, the CD14(+) cell fraction was the main source of IL-10 production upon interaction with LAB. CONCLUSION: Our results indicate that certain strains of lactobacilli and bifidobacteria modulate the production of cytokines by monocytes and lymphocytes, and may divert the immune system in a regulatory or tolerant mode. These specific strains may be favorable to use in prevention or treatment of atopic disease.     

The impact of dydrogesterone supplementation on serum cytokine profile in women with threatened abortion

PROBLEM: The role of increased Th1 cytokine expression in pregnancy failure has been questioned recently. The therapeutic value of progestogens in threatened abortion (TA) is still debated. The aim of this prospective study was to compare serum cytokine [tumor necrosis factor (TNF)-alpha, interleukin (IL)-12 and IL-10] concentrations in women with TA to those in women with normal pregnancy and to evaluate the impact of dydrogesterone supplementation in the former group on cytokine concentration. METHODS OF STUDY: Twenty-seven threatened aborters were treated for 10 days with dydrogesterone (30-40 mg/day). Sixteen healthy pregnant controls received no treatment. Serum cytokine concentrations were measured twice in both groups by enzyme-linked immunosorbent assay. RESULTS: Mean serum concentrations of Th1- and Th2-type cytokines in women with TA did not differ from those in women with normal pregnancy at first and second sampling. After dydrogesterone supplementation, mean TNF-alpha/IL-10 ratio changed from 1.08 to 1.75 while IL-12/IL-10 ratio remained almost the same (0.56-0.61) in the threatened aborters group and did not differ from those in healthy women. CONCLUSIONS: The results of this study indicate that peripheral cytokine production in threatened aborters does not differ from that observed among healthy pregnant women. The protective effect of dydrogesterone supplementation in threatened aborters is manifested via restoring progesterone-induced blocking factor concentration rather than controlling cytokine production.     

Immunomodulatory effects of peptide T on Th 1/Th 2 cytokines.

Peptide T is an octapeptide from the V2 region of HIV-1 gp120. It has been shown to resolve psoriatic lesions--an inflammatory skin disease. The mechanisms of anti-inflammatory actions of peptide T are not well understood. Th1 cytokines such as IL-2, and IFN-gamma are upregulated in psoriasis. These cytokines play a key role in the inflammatory and proliferative processes of psoriasis. The effects of peptide T on Th1 and Th2 cytokines were studied in order to elucidate the mechanisms of antiinflammatory actions of peptide T. It was observed that peptide T at 10(-8) M induces IL-10 production by the human Th2 cell line and PBMC (P < 0.05, ANOVA). Also peptide T at 10(-9) M concentration significantly inhibited IFN-gamma production by PBMC (P < 0.001, ANOVA). Anti IL-10 antibody inhibited the anti-IFN-gamma effect of peptide T (P < 0.05, t-test). Our study shows that peptide T induces IL-10 production and inhibits IFN-gamma production. IL-10 is a potent anti-inflammatory cytokine. It inhibits IL-2 and IFN-gamma production from the T cells and downregulates the expression of TNF-alpha in the antigen presenting cells. Recently, IL-10 has been shown to resolve psoriatic lesions. The effects of peptide T on IL-10 and IFN-gamma production provides a plausible explanation for its clinical efficacy in psoriasis.     

IL-15 in human visceral leishmaniasis caused by Leishmania infantum

Interleukin (IL)-15 is a recently discovered cytokine with the ability to stimulate the proliferation activity of Th1 and/or Th2 lymphocytes. Here, we investigated the involvement of IL-15 in the immune response to Leishmania infantum infection by studying patients with visceral leishmaniasis (VL). We found that IL-15 is produced by leishmanial antigen (LAg)-stimulated peripheral blood mononuclear cells (PBMC) from active VL patients at a significantly higher level than those produced by cells from healed VL subjects or healthy controls. A significant increase in IL-15 serum blood levels was also observed in acute VL patients compared with healed ones. Furthermore, recombinant IL-15 had an appreciable effect in vitro in reducing IL-4 and increasing the production of IL-12 in response to LAg, but it was ineffective in altering the production of interferon-gamma (IFN-gamma). The production of endogenous IL-15 in acute VL patients appeared to be insufficient to activate both IFN-gamma and IL-12, as attested by the absence of modification of these two cytokines by neutralization experiments in the presence of anti-IL-15 monoclonal antibodies (MoAB). On the contrary, the neutralization of IL-15 increased IL-4 production. Together, these results indicate that endogenous IL-15 plays a role in the suppression of Th2-type cytokines, even though it does not enhance the production of Th1 cytokines in acute VL patients. Since IL-15, in the presence of anti-IL-4 MoAb, caused a further increase in IL-12 production and led to a significant production of IFN-gamma, one of its indirect effects on Th1 cell activation could be due to the latter's effect on Th2 cytokines such as IL-4. Therefore, our observations indicate that there is a potential for IL-15 to augment the T-cell response to human intracellular pathogens.     

Investigation of possible cytokine induction in peripheral blood mononuclear cells by heat-stable serotypes of Campylobacter jejuni

Several Campylobacter jejuni heat-stable (HS) serotypes have been associated with the autoimmune Guillain-Barre neurological syndrome (GBS). In order to examine the possible involvement of cytokines in this phenomenon, the levels of three pro-inflammatory cytokines (interleukin (IL)-2sRa, IL-6 and interferon (IFN)-gamma) and one anti-inflammatory cytokine (IL-10) were measured in peripheral blood mononuclear cells after induction by different C. jejuni serotypes. No differences were found for IL-6, IFN-gamma and IL-10, but the non-sialylated serotype HS:3 was associated with decreased production of IL-2sRa. The results raise the possibility that absence of sialylation might be associated with the inability to induce inflammatory factors such as cytokines.