Pattern Of Cytokine Production Research Articles

Role of MAPK Kinase 6 in Arthritis: Distinct Mechanism of Action in Inflammation and Cytokine Expression

Development of p38alpha inhibitors for rheumatoid arthritis has been hindered by toxicity and limited efficacy. Therefore, we evaluated whether MKK6, an upstream kinase that regulates multiple p38 isoforms, might be an alternative therapeutic target in inflammatory arthritis. Wild-type (WT), MKK6(-/-), and MKK3(-/-) mice were administered K/BxN serum to induce arthritis. Articular expression of activated kinases and cytokines was determined by Western blot, qPCR, ELISA, and multiplex analysis. Immunoprecipitation and confocal microscopy experiments were performed to determine the subcellular location of MKK6, P-p38, and MAPKAPK2 (MK2). Arthritis scores were significantly lower in MKK6(-/-) mice compared with WT mice. Joint destruction and osteoclast differentiation were lower in MKK6(-/-), as were articular IL-6 and matrix metalloproteinase-3 expression. Phospho-p38 levels were modestly decreased in the joints of arthritic MKK6(-/-) mice compared with WT but were significantly higher than MKK3(-/-) mice. P-MK2 was low in MKK6(-/-) and MKK3(-/-) mice. Uncoupled p38 and MK2 activation was also observed in cultured, MKK6(-/-) FLS and confirmed using kinase assays. Immunoprecipitation assays and confocal microscopy showed that P-p38 and MK2 colocalized in activated WT but not MKK6(-/-) FLS. Distinct patterns of cytokine production were observed in MKK6(-/-) and MKK3(-/-) cells. MKK6 deficiency suppresses inflammatory arthritis and joint destruction, suggesting it might be a therapeutic target for inflammation. Although MKK3 and MKK6 activate the p38 pathway, they regulate distinct subsets of proinflammatory cytokines. MKK6 appears mainly to facilitate p38 and MK2 colocalization in the nucleus rather than to phosphorylate p38.

Local and Systemic Activation of the Mononuclear Phagocyte System in Aseptic Loosening of Total Hip Arthroplasty

Osteoarticular prosthesis loosening involves recruitment, activation, and differentiation of mononuclear phagocytes, with a complex and still unclear interplay of local and systemic inflammation. We hypothesized that aseptic hip prosthesis loosening is bound to a coordinated systemic and local activation of the mononuclear phagocyte system (MPS), which can be demonstrated by simultaneous assessment of both compartments. We, therefore, compared systemic and synovial inflammatory cytokines, circulating monocyte activation state, and synovial fluid (SF) ability to induce osteoclastic differentiation. Twenty-seven patients undergoing total hip replacement for aseptic loosening were compared to 30 patients receiving total hip prosthesis for primary osteoarthritis. SF from aseptic loosening patients induced a more effective osteoclast-like differentiation of monocytic THP-1 cells in vitro and a proinflammatory pattern of cytokine production in these osteoclast-like cultures. On the contrary, SF from osteoarthritis patients did not favor osteoclastogenesis and exerted an anti-inflammatory effect through IL-10 upregulation and TNF-alpha inhibition. Peripheral blood monocytes of aseptic loosening patients were primed for activation, with higher TNF-alpha responses than their counterparts in the osteoarthritis group. Finally, cytokine enrichment in SF versus serum was observed in both patient groups: a fivefold increase in synovial TNF-alpha in aseptic loosening patients and a 14-fold increase in synovial IL-10 in osteoarthritis patients. The TNF-alpha/IL-10 ratio was elevated in both systemic and synovial settings from aseptic loosening patients with respect to osteoarthritis patients. Taken together, our results demonstrate the integrated activation of the MPS and suggest the possible use of cytokines in the laboratory workup of prosthesis aseptic loosening.

Galectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways

High expression of galectin 3 at sites of joint destruction in rheumatoid arthritis (RA) suggests that galectin 3 plays a role in RA pathogenesis. Previous studies have demonstrated the effects of galectins on immune cells, such as lymphocytes and macrophages. This study was undertaken to investigate the hypothesis that galectin 3 induces proinflammatory effects in RA by modulating the pattern of cytokine and chemokine production in synovial fibroblasts. Matched samples of RA synovial and skin fibroblasts were pretreated with galectin 3 or tumor necrosis factor alpha (TNFalpha), and the levels of a panel of cytokines, chemokines, and matrix metalloproteinases (MMPs) were determined using enzyme-linked immunosorbent assays and multiplex assays. Specific inhibitors were used to dissect signaling pathways, which were confirmed by Western blotting and NF-kappaB activation assay. Galectin 3 induced secretion of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, CXCL8, and MMP-3 in both synovial and skin fibroblasts. By contrast, galectin 3-induced secretion of TNFalpha, CCL2, CCL3, and CCL5 was significantly greater in synovial fibroblasts than in skin fibroblasts. TNFalpha blockade ruled out autocrine TNFalpha-stimulated induction of chemokines. The MAPKs p38, JNK, and ERK were necessary for IL-6 production, but phosphatidylinositol 3-kinase (PI 3-kinase) was required for selective CCL5 induction. NF-kappaB activation was required for production of both IL-6 and CCL5. Our findings indicate that galectin 3 promotes proinflammatory cytokine secretion by tissue fibroblasts. However, galectin 3 induces the production of mononuclear cell-recruiting chemokines uniquely from synovial fibroblasts, but not matched skin fibroblasts, via a PI 3-kinase signaling pathway. These data provide further evidence of the role of synovial fibroblasts in regulating the pattern and persistence of the inflammatory infiltrate in RA and suggest a new and important functional consequence of the observed high expression of galectin 3 in the rheumatoid synovium.

TH1/TH2 balance in concomitant immediate and delayed-type hypersensitivity diseases

In spite of the observation of mutual inhibitory properties of TH1 and TH2 CD4+ cells, a group of patients developed simultaneously immediate and delayed-type hypersensitivity reactions that are theoretically antagonistic. Patients presenting concomitant hypersensitivity reactions were evaluated for cytokine production. PBMC from 45 patients and 13 non-atopic individuals were cultured with mite allergen and mitogen and the supernatants obtained were evaluated for cytokine production by ELISA. The analysis of the cytokines levels revealed increased production of pro-inflammatory cytokine TNF-α in the non-atopic individuals after specific and mitogen stimulus. The IL-4 was largely observed on serum samples and IL-5 levels were higher in the double sensitized group (group DerpNi) after PHA stimulus. The IL-13 levels were increased in sensitized groups (Derp and DerpNi groups) after PHA stimuli. Atopic patients (Derp and DerpNi groups) presented lowest levels IFN-γ and the analysis of TGF-β production after rDER P I stimulation have shown increased levels among sensitized patients to Dermatophagoides pteronyssinus mite. IL-10 levels did not differ after antigen stimulation but basal production was higher on Derp and DerpNi groups. Furthermore, negative correlations were observed between IFN-γ levels and IL-4, IL-13 and IL-10. This study has shown patients able to react, concomitantly, to the two types of antigens – rDER P I and NiSO4, present distinct pattern of cytokine production. The increased levels of IL-13 in the sensitive individuals to mite antigen (rDER P I) and IFN-γ in NiSO4 sensitized individuals confirm the role of the type TH2 response in the atopies and TH1 type in DCA.

Relevance of Gamma Interferon, Tumor Necrosis Factor Alpha, and Interleukin-10 Gene Polymorphisms to Susceptibility to Mediterranean Spotted Fever

The acute phase of Mediterranean spotted fever (MSF) is characterized by dramatic changes in cytokine production patterns, clearly indicating their role in the immunomodulation of the response against the microorganism, and the differences in cytokine production seem to influence the extent and severity of the disease. In this study, the single nucleotide polymorphisms (SNPs) of tumor necrosis factor alpha (TNF-alpha) -308G/A (rs1800629) and interleukin-10 (IL-10) -1087G/A (rs1800896), -824C/T (rs1800871), and -597C/A (rs1800872) and the gamma interferon (IFN-gamma) T/A SNP at position +874 (rs2430561) were typed in 80 Sicilian patients affected by MSF and in 288 control subjects matched for age, gender, and geographic origin. No significant differences in TNF-alpha -308G/A genotype frequencies were observed. The +874TT genotype, associated with an increased production of IFN-gamma, was found to be significantly less frequent in MSF patients than in the control group (odds ratio [OR], 0.18; 95% confidence interval [95% CI], 0.06 to 0.51; P corrected for the number of genotypes [Pc], 0.0021). In addition, when evaluating the IFN-gamma and IL-10 genotype interaction, a significant increase of +874AA/-597CA (OR, 5.31; 95% CI, 2.37 to 11.88; P(c), 0.0027) combined genotypes was observed. In conclusion, our data strongly suggest that finely genetically tuned cytokine production may play a crucial role in the regulation of the immune response against rickettsial infection, therefore influencing the disease outcomes, ranging from nonapparent or subclinical condition to overt or fatal disease.

Evaluation of reduced allergenicity of irradiated peanut extract using splenocytes from peanut-sensitized mice

Peanut (PN) allergy is one of the most serious forms of IgE-mediated food hypersensitivity. Gamma irradiation has been widely used for the preservation of food. The results of our previous studies showed that the IgE-binding capacity to several antigens were profoundly reduced after gamma irradiation. In this study, we evaluated the changes of allergenecity and cytokine production profiles after exposure of irradiated PN extract in a PN-allergy mouse model. Mice were sensitized to PN extract by intragastric administration on days 0, 1, 2, and 7, and then challenged on day 21. Four weeks later, we evaluated the cytokine production patterns and proliferation responses of splenocytes that were stimulated with intact PN extract, compared to 10 and 50 kGy irradiated PN extract. When the cells were stimulated with 10 kGy of irradiated PN extract, a higher level of production of IFN-γ and IL-10 cytokines was observed. However, stimulation with 50 kGy of irradiated PN extract resulted in a higher level of production of only IFN-γ cytokines. In addition, the Th1/Th2 ratio increased in response to treatment with gamma-irradiated PNs. The results of this study show that the allergenicity of PN extracts could be reduced by gamma irradiation which caused downregulation of Th2 lymphocyte activity in the PN-sensitized mice.

Postthymic maturation influences the CD8 T cell response to antigen

Complete T cell development requires postthymic maturation, and we investigated the influence of this ontological period on the CD8 T cell response to infection by comparing responses of mature CD8 T cells with those of recent thymic emigrants (RTEs). When activated with a noninflammatory stimulus or a bacterial or viral pathogen, CD8 RTEs generated a lower proportion of cytokine-producing effector cells and long-lived memory precursors compared with their mature counterparts. Although peripheral T cell maturation is complete within several weeks after thymic egress, RTE-derived memory cells continued to express inappropriate levels of memory cell markers and display an altered pattern of cytokine production, even 8 weeks after infection. When rechallenged, RTE-derived memory cells generated secondary effector cells that were phenotypically and functionally equivalent to those generated by their mature counterparts. The defects at the effector and memory stages were not associated with differences in the expression of T cell receptor-, costimulation-, or activation-associated cell surface markers yet were associated with lower Ly6C expression levels at the effector stage. This work demonstrates that the stage of postthymic maturation influences cell fate decisions and cytokine profiles of stimulated CD8 T cells, with repercussions that are apparent long after cells have progressed from the RTE compartment.

Pattern and diversity of cytokine production differentiates between Mycobacterium tuberculosis infection and disease

Tuberculosis (TB) remains a global health problem. The solution involves development of an effective vaccine, but has been limited by incomplete understanding of what constitutes protective immunity during natural infection with Mycobacterium tuberculosis. In this study, M. tuberculosis-specific responses following an overnight whole-blood assay were assessed by intracellular cytokine staining and luminex, and compared between TB cases and exposed household contacts. TB cases had significantly higher levels of IFN-gamma(+)TNF-alpha(+)IL-2(+)CD4(+)T cells compared with contacts. TB cases also had a significantly higher proportion of cells single-positive for TNF-alpha, but lower proportion of cells producing IL-2 alone and these differences were seen for both CD4(+)and CD8(+) T cells. Cytokine profiles from culture supernatants were significantly biased toward a Th1 phenotype (IFN-gamma and IL-12(p40)) together with a complete abrogation of IL-17 secretion in TB cases. Our data indicate that despite a robust response to TB antigens in active TB disease, changes in the pattern of cytokine production between TB infection and disease clearly contribute to disease progression.

Cord Blood Cytokines are Modulated by Maternal Farming Activities and Consumption of Farm Products during Pregnancy - The PASTURE-Study

RATIONALE: Since traditional farming represents a unique model situation to investigate the relationship of early-life microbial exposure and allergy protection. associations between maternal farming exposures and cytokine production in cord blood mononuclear cells in a prospective multi-national birth cohort of 530 farm and 603 non-farm children and their families.METHODS: Supernatants from stimulated CB mononuclear cells were assessed for the production of IL-5, IFN-γ, IL-10 IL-12 and TNF-α by using ELISA-assays. Associations between maternal farming exposures and the porduction of cord blood cytokines were assessed by using a Tobit-regression model.RESULTS: Cord blood from farmer children showed significantly higher levels of TNF-α and IFN-γ production compared to cord blood non-farmer children, whereas IL-10, IL-12 and IL-5 levels did not differ between these study groups. Elevated TNF-α and IFN-γ levels in cord blood were associated with maternal exposures to farm animals, animal sheds, hay lofts, farm milk and farm milk products during pregnancy.CONCLUSIONS: Maternal exposure to farming activities and farm products during pregnancy modulated cytokine production patterns of their offspring at birth. RATIONALE: Since traditional farming represents a unique model situation to investigate the relationship of early-life microbial exposure and allergy protection. associations between maternal farming exposures and cytokine production in cord blood mononuclear cells in a prospective multi-national birth cohort of 530 farm and 603 non-farm children and their families. METHODS: Supernatants from stimulated CB mononuclear cells were assessed for the production of IL-5, IFN-γ, IL-10 IL-12 and TNF-α by using ELISA-assays. Associations between maternal farming exposures and the porduction of cord blood cytokines were assessed by using a Tobit-regression model. RESULTS: Cord blood from farmer children showed significantly higher levels of TNF-α and IFN-γ production compared to cord blood non-farmer children, whereas IL-10, IL-12 and IL-5 levels did not differ between these study groups. Elevated TNF-α and IFN-γ levels in cord blood were associated with maternal exposures to farm animals, animal sheds, hay lofts, farm milk and farm milk products during pregnancy. CONCLUSIONS: Maternal exposure to farming activities and farm products during pregnancy modulated cytokine production patterns of their offspring at birth.

Analysis of Helper T Cell Responses to Cry j 1-Derived Peptides in Patients with Nasal Allergy: Candidate for Peptide-Based Immunotherapy of Japanese Cedar Pollinosis

Allergen specific immunotherapy is highly effective, but adverse events may occur during treatment. Peptide-based immunotherapy has been proposed as one of new strategies for reduction of allergic adverse reactions. We examined the possibility of candidate peptides for the development of peptide-based immunotherapy for Japanese cedar pollinosis. Twelve Cry j 1-specific T-cell lines were established from peripheral blood mononuclear cells (PBMC) of 12 patients with Japanese cedar pollinosis. Using these T-cell lines, 37 Cry j 1-derived overlapping peptides were assessed for their proliferative responses and cytokine production. Four peptides corresponding to the Cry j 1 sequence were able to induce proliferative responses to more than one T-cell line: p61-80 (3/12; 25.0%); p115-132 (2/12; 16.6%); p206-225 (4/12; 33.3%); and p337-353 (5/12; 41.7%). Furthermore, T-cell lines generated from 11 of 12 donors (91.7%) responded to at least one of these four peptides. On the other hand, the pattern of cytokine production from Cry j 1-specific T-cell lines varied. Moreover, cytokine production patterns by stimulation with Cry j 1 peptide did not reflect those by stimulation with Cry j 1 protein. Our results suggest four Cry j 1-derived peptides (p61-80, p115-132, p206-225 and p337-353) may be considered to be the immunodominant T-cell epitopes of the Cry j 1 molecule, and can be useful for the design of peptide-based immunotherapy for the management of Japanese cedar pollinosis.

Quantitative Differences in Immune Responses in Mouse Strains that Differ in their Susceptibility to Trypanosoma brucei brucei Infection

We compared the relative resistance and soluble variant surface glycoprotein (VSG)-specific responses in (C57BL/6 x BALB/c)-F1 (B6B-F1) and C3H mice during infection with Trypanosoma brucei brucei, the hemoprotozoan parasite causing a debilitating disease in man and livestock. We demonstrated that C3H mice are relatively more trypanosusceptible, as evidenced by their reduced ability to control parasitemia and shorter survival time, than B6B-F1 mice. Quantitative differences in the pattern of cytokine and antibody (Ab) production were observed between the 2 mouse strains following infection with T. b. brucei. Thus, although both mouse strains recorded detectable levels of IFN-gamma, TNF-alpha, NO and IL-10 in plasma and lymph nodes, as well as plasma IgM, IgG1, IgG2a, IgG2b and IgG3 Abs against VSG, the susceptible C3H mice only exhibited trace levels of Abs of all isotypes and yet produced elevated levels of IFN-gamma, TNF-alpha and NO, compared to the relatively trypanotolerant B6B-F1 mice. In aggregate, these data strongly suggest that trypanosome-infected C3H mice have an immunological defect, manifested not only by suppression at the B cell clonal level, but also at the level of protective T cell and macrophage phenotypes.

Effect of Amblyomma cajennense Ticks on the Immune Response of BALB/c Mice and Horses

This work evaluated the effect of the Amblyomma cajennense tick on the immune response of BALB/c mice and on horse lymph node cell proliferation. We observed that mice do not develop resistance to nymphs of this tick species and that lymphocyte proliferation of this host is inhibited by tick saliva, nymphal extract, or infestations. Horse lymph node cell proliferation is inhibited by tick saliva as well. Mice lymphocytes under the effect of tick saliva, nymphal extract, or infestations display a predominantly Th-2 cytokine production pattern. Observed results partially explain this tick's disease vectoring capacity and broad host range.

Intestinal Bifidobacterium association in germ-free T cell receptor transgenic mice down-regulates dietary antigen-specific immune responses of the small intestine but enhances those of the large intestine

Bifidobacterium is a dominant bacterial species among commensals in the human intestine and is thought to have probiotic immunomodulatory effects. In this study, we investigated the effect of the association with Bifidobacterium pseudocatenulatum JCM 7041 (Bp) on dietary ovalbumin (OVA)-specific immune responses using germ-free OVA-specific T cell receptor transgenic mice (OVA23-3 mice). We established germ-free OVA23-3 mice, and then associated with Bp (BIF group) or without (CONT group) and additionally associated with segmented filamentous bacteria (SFB) and clostridia in both groups. BIF and CONT mice were fed an egg-white diet containing OVA for 1 week. Cytokine production in response to OVA by cells of Peyer's patches (PPs) and lamina propria (LP) from the small and large intestine was measured. Interferon (IFN)- γ and interleukin (IL)-6 production by PP cells from BIF group mice was lower than that of the CONT group. The proportion of PP cells expressing CD4 +CD62L low, an activated/memory T cell phenotype, was higher in BIF group mice than the CONT group. Furthermore, LP cells from the small intestine in Bp-associated mice showed a tendency to produce slightly lower IFN- γ and IL-6, while the cells from large intestine produced markedly higher IFN- γ, IL-5 and IL-6 than those in the CONT group. The pattern of cytokine production by PP in BIF animals was similar to those isolated from conventional mice. These results suggest that intestinal association with Bp might down-regulate excessive immune responses to dietary antigens of the small intestine but enhance those of the large intestine.

ORIGINAL ARTICLE: Characterization of Cytokine Production by Human Term Placenta Macrophages In Vitro

Problem Macrophages are apparently the only immune cells within placenta villi, yet functions of these cells remain obscure. It has been postulated that placental macrophages accomplish regulatory roles at the fetal–maternal interface by means of wide variety of secreted cytokines. We attempt to analyze the patterns of cytokine production in an isolated population of placental macrophages.Method of study Macrophages were obtained from term placentas in the absence of spontaneous labor. The basal and lipopolysaccharide (LPS)‐stimulated levels of intracellular cytokines were detected by flow cytometry. The basal cytokine secretion was determined by BD™Cytometry Bead Array (BD Biosciences, San Diego, CA, USA).Results Intracellular IL‐1α, IL‐1β, IL‐6, and TNFα were detected in 31, 27, 4, and 3% CD68+ cells, respectively. Stimulation with LPS increased the proportions of cytokine‐producing CD68+ cells to 48, 50, 28, and 49%, respectively. Under basal conditions, levels of released TNFα and IL‐6, respectively, were 20‐ and 25‐fold higher when compared with IL‐1β while IL‐10 was secreted in small but detectable amounts. When a secretory activity was estimated for cytokine‐producing cells, the secretion rate for TNFα and IL‐6 overwhelmingly surpassed that for IL‐1β (TNFα:IL‐6:IL‐1β ratio was 192:145:1).Conclusion These results suggest functional heterogeneity of the placental macrophage population and contribute to the elucidation of regulatory roles of these cells in gestation.

Tumor Antigen-specific T-cells are Present in the CD8αα+ T-cell Effector-memory Pool

CD8+ T-cell memory formation has recently been demonstrated to be associated with CD8alphaalpha homodimer expression by T-cells in mice. Up to now, the knowledge about the clinical significance of CD8alphaalpha+ T-cells in humans is limited. We assessed in longitudinally collected blood samples from patients with melanoma, who underwent a peptide-based vaccination, the role of CD8alphaalpha+ T-cells in tumor-specific cellular immune responses. Phenotypic analysis showed that the expression of CD8alphaalpha+ by T-cells was stable over time and associated with a CD45RA+/-CCR7- effector-memory profile. Melan-A/MART-1-specific T-cells were identified in the CD8alphaalpha+ T-cell compartment by tetramer technology. Detection of intracellular cytokine production (interleukin-2, interferon-gamma, and tumor necrosis factor-alpha) upon phorbol 12-myristate 13-acetate-ionomycin stimulation in CD8alphaalpha+ and CD8alphabeta+ T-cells revealed that CD8alphaalpha+ T-cells show a unique cytokine production pattern (tumor necrosis factor-alpha and interferon-gamma production) as compared with CD8alphabeta+ T-cells. T-cell receptor-CDR3 length analysis revealed that Melan-A/MART-1-specific CD8alphaalpha+ T-cells showed a similar T-cell receptor-repertoire as compared with Melan-A/MART-1-specific CD8alphabeta+ T-cells. Our results show that CD8alphaalpha+ T-cells represent a compartment of CD45RA+/- effector-memory cells in the peripheral circulation of patients with melanoma and suggest that CD8alphaalpha T-cells may originate from CD8+ T-cells that have down-regulated the expression of the CD8beta chain. CD8alphaalpha+ and tetramer-specific T-cells may represent a valuable marker to gauge long-term antigen-specific T-cell memory.

Toll‐like receptor 2 agonist Pam3CSK4 enhances the induction of antigen‐specific tolerance via the sublingual route

Sublingual immunotherapy (SLIT) has been established in humans as a safe and efficacious treatment for type I respiratory allergies. In this study, we compared three Toll-like receptor (TLR) 2 ligands (Pam3CSK4, Porphyromonas gingivalis lipopolysaccharide and lipoteichoic acid) as potential adjuvants for sublingual allergy vaccines. These molecules were tested in co-cultures of adjuvant-pre-treated dendritic cells (DCs) with murine naïve CD4(+) T lymphocytes. Patterns of cytokine production, phenotype, proliferation and gene expression were analysed by ELISA, cytofluorometry and quantitative PCR, respectively. TLR2 ligands were subsequently tested in a model of SLIT in BALB/c mice sensitized with ovalbumin (OVA). Among the three TLR2 ligands tested, the synthetic lipopeptide Pam3CSK4 is the most potent inducer of IL-12p35 and IL-10 gene expression in murine bone marrow-derived DCs, as well as in purified oral myeloid DCs. Only Pam3CSK4-treated DCs induce IFN-gamma and IL-10 secretion by naïve CD4(+) T cells. Sublingual administration of Pam3CSK4 together with the antigen in BALB/c mice sensitized to OVA decreases airway hyperresponsiveness as well as OVA-specific T-helper type 2 (Th2) responses in cervical lymph nodes dramatically. Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.

Profile of Serum IL-1β and IL-10 Shortly after Ovariectomy and Estradiol Replacement in Rats

Ovariectomy leads to progressive and significant increases in body weight gain and osteoporosis and is related to changes in serum and tissue cytokine profiles, such as observed in other models of overweight. We aimed to evaluate serum interleukin-1beta and interleukin-10 shortly after ovariectomy, before the establishment of overweight in rats. Female Wistar rats were submitted to ovariectomy, ovariectomy and estradiol replacement, or sham operation and compared with intact controls. Rats were killed 3, 6, 9, or 13 d after ovariectomy. Body mass and retroperitoneal fats were significant higher only 13 d after ovariectomy, and estradiol replacement to ovariectomized rats impaired both body mass and retroperitoneal fat gain. Shortly after ovariectomy (at 3 d) serum interleukin-1beta levels significantly increased in ovariectomized rats, treated or not with estradiol, while serum interleukin-10 levels increased only 9 d after ovariectomy. Our results suggest the existence of an important interplay between the immune system and ovarian function. This interplay occurs regardless of significant changes in adipose tissue compartment, as ovarian excision leads to short-term changes in the pattern of interleukin-1beta and interleukin-10 cytokine production that precede body weight gain and are not reverted by estradiol replacement.

IL-18 is correlated with type-2 immune response in children with steroid sensitive nephrotic syndrome

Children with steroid sensitive nephrotic syndrome (SSNS) is thought to have dysregulated type-1/type-2 cytokine network. Interleukin (IL)-18 is a cytokine, which may enhance both type-1 and type-2 responses, depending on the cytokines milieu. This prospective study aimed to assess type-1/type-2 cytokine synthesis and production profile in different stages of SSNS and define the potent involvement of IL-18. Twenty-three children with SSNS, aged 2.5–14 years, were studied; 23/23 both in active stage before treatment initiation and in remission still on steroids; 15/23 in remission off steroids as well. Data were compared with those obtained from 25 age-matched controls. The following parameters were assessed: Basic T cell populations, percentages of CD3+/CD69+/IFN-γ+ and CD3+/CD69+/IL-4+ T cells as well as serum levels of IFN-γ, IL-2, IL-4, IL-13 and IL-18. No difference in IL-2 levels was found between nephrotic children of all disease stages and controls ( p > 0.05). Percentage of CD3+/CD69+/IL-4+ T cells and serum levels of IL-4, IL-13 and IL-18 were significantly higher in the active stage of SSNS compared with the remission stages and controls ( p < 0.05). On the contrary, percentage of CD3+/CD69+/IFN-γ+ T cells as well as serum IFN-γ were significantly lower during active disease stage compared with remission stages and controls ( p < 0.05). In children with SSNS, of all disease stages, serum levels of IL-18 were significantly correlated with both IL-4 and IL-13 ( r = 0.628 and p < 0.0001, r = 0.71 and p < 0.0001, respectively). It seems that a type-2 cytokine synthesis and production pattern prevails in children with active SSNS and IL-18 expression is significantly correlated with this type-2 immune response.

CD4 T cells: fates, functions, and faults

AbstractIn 1986, Mosmann and Coffman identified 2 subsets of activated CD4 T cells, Th1 and Th2 cells, which differed from each other in their pattern of cytokine production and their functions. Our understanding of the importance of the distinct differentiated forms of CD4 T cells and of the mechanisms through which they achieve their differentiated state has greatly expanded over the past 2 decades. Today at least 4 distinct CD4 T-cell subsets have been shown to exist, Th1, Th2, Th17, and iTreg cells. Here we summarize much of what is known about the 4 subsets, including the history of their discovery, their unique cytokine products and related functions, their distinctive expression of cell surface receptors and their characteristic transcription factors, the regulation of their fate determination, and the consequences of their abnormal activation.

Unique Impacts of HBV Co-infection on Clinical and Laboratory Findings in a Recent Dengue Outbreak in China

High prevalence of hepatitis B virus (HBV) infection in China offers a unique setting to examine HBV's influence on the presentation of dengue fever. In 398 patients admitted for suspected dengue fever, 89% (353/398) were positive for dengue IgM antibodies. Among dengue-infected patients, 8% (29/353) had chronic HBV co-infection. Only dengue virus serotype 1 was identified by virus isolation and reverse transcriptase-polymerase chain reaction assays. No case of dengue hemorrhagic fever/dengue shock syndrome was diagnosed. In addition to routine clinical tests, interleukin 2 (IL-2), IL-4, IL-6, IL-10, interferon gamma (IFNgamma), and tumor necrosis factor alpha (TNFalpha) levels were measured in the sera of 95% (334/353) of dengue-infected subjects as well as controls. Surprisingly, HBV/dengue co-infected patients made less IL-6 (P < 0.05) and TNFalpha (P < 0.05) than patients with only dengue infection. Similar levels of IL-4, IL-10, and IFNgamma were found in both groups. Thus, HBV co-infection seems to alter the cytokine production pattern when patients contract dengue infection.