IL-2 and IL-15 play an important roles in regulating the lymphocyte function and homeostasis. Advances in understanding of the cellular and molecular biology of IL-2 and IL-15 and their receptor complex have provided rationale to better utilize them to expand and activate immune effectors in patients with cancer. These two cytokines stimulate similar responses from lymphocytes in vitro, but play markedly distinct roles in lymphoid biology in vivo. Their distinct physiological functions can be ascribed to distinct signaling pathways initiated by distinct cytokine receptor subunits, differential expression patterns of their receptors. Recently, the discovery of a novel mechanism of IL-15 cytokine signaling, trans-presentation, has provided insights into the divergent ways of these cytokine function. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin 2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin 15 is dedicated to the prolonged maintenance of memory T-cell responses to pathogens. As discussed in this article, the biology of IL-2 and IL-15 two cytokines will affect the development of novel treatment for malignancies and autoimmune diseases.
Humans ; Immunotherapy ; Interleukin-15 ; immunology ; metabolism ; Interleukin-2 ; immunology ; metabolism

OBJECTIVETo investigate the effect of secondary lymphoid tissue chemokine (SLC) on experimental colon lesions in rats with ulcerative colitis.

METHODSSixty Sprague-Dawley rats were randomly divided into control group, model group and SLC intervention group. Colonic mucosal lesions of different groups were observed with HE staining for inflammation and lymphocyte homing situation. Cytokine IL-2 and IL-6 levels were measured by ABC-ELISA. Semi-quantitative RT-PCR was used to examine the colonic SLC expression.

RESULTSIntestinal inflammation score and colonic cytokine levels were significantly different among three groups (P<0.05, P<0.01). Abnormal lymphocyte homing phenomenon under colonic mucosa was found in the model group and the intervention group. SLC mRNA expression of the model and intervention groups increased significantly compared with the control group (0.846+/-0.047, 0.768+/-0.135 vs 0.312+/-0.112, P<0.01). However, there was no significant difference between model group and intervention group.

CONCLUSIONSSLC may play an important role in experimental colonic mucosal inflammation in rats with ulcerative colitis. Blockade of SLC may be one of effective ways in reducing colonic mucosal inflammation.

Animals ; Chemokine CCL21 ; metabolism ; Colitis, Ulcerative ; metabolism ; physiopathology ; Female ; Inflammation ; Interleukin-2 ; metabolism ; Interleukin-6 ; metabolism ; Rats ; Rats, Sprague-Dawley

This study was aimed to explore the killing effect of PBMNC induced by IL-23 alone or combined with IL-2 on K562 cells and its mechanism. The PBMNC were induced in vitro by IL-23 (50 ng/ml) alone or IL-23 combined with IL-2 (100 U/ml) for 72 h, and then were co-cultured with leukemia cell line K562. The CCK-8 method was used to detect the effect of PBMNC induced at different times on K562 cells, the ELISA was performed for detecting IFN-γ level in culture supernatant, and the perforin and granzymes B were detected by RQ-PCR. The results showed that the killing effect of PBMNC induced by IL-23 alone or IL-23 combined with IL-2 on K562 cells was observed, and obviously enhanced with prolonging of time, moreover, there was statistical difference among different time points (P < 0.05). The IFN-γ level in supernatant of PBMNC cultured with cytokines significantly increased, and the IFN-γ levels in group of IL-23 combined with IL-2 were higher than that in other groups (P < 0.05). The mRNA expressions level of perforin and granzymes B of the expanded PBMNC in groups cultured with cytokines were higher than that in control group (P < 0.05), and the mRNA expressions of perforin and granzymes B in group of IL-23 combined with IL-2 were significantly higher than that in others (P < 0.05). It is concluded that IL-23 can promote the killing effect of PBMNC on K562 cells. The combination of IL-2 with IL-23 displays synergic effect and a time-dependent manner. IL-23 also enhances the expression of IFN-γ, perforin and granzyme B in PBMNC. Its combination with IL-2 displays synergistic effect, suggesting that the anti-leukemic activity of IL-23 may be realized through inducing PBMNC to express IFN-γ, perforin and granzyme B.
Granzymes ; metabolism ; Humans ; Interferon-gamma ; metabolism ; Interleukin-2 ; pharmacology ; Interleukin-23 ; pharmacology ; K562 Cells ; Monocytes ; drug effects ; metabolism ; Perforin ; metabolism

Bile Ducts, Intrahepatic ; metabolism ; Humans ; Interleukin-2 Receptor alpha Subunit ; metabolism ; Liver ; metabolism

OBJECTIVE: Schizophrenia is a disabling disorder of unknown aetiology, lacking definite diagnostic method and cure. A reliable biological marker of schizophrenia is highly demanded, for which traceable immune mediators in blood could be promising candidates. We aimed to gather the best findings of neuroinflammatory markers for first-episode psychosis (FEP). METHODS: We performed an extensive narrative review of online literature on inflammation-related markers found in human FEP patients only. RESULTS: Changes to cytokine levels have been increasingly reported in schizophrenia. The peripheral levels of IL-1 (or its receptor antagonist), soluble IL-2 receptor, IL-4, IL-6, IL-8, and TNF-α have been frequently reported as increased in FEP, in a suggestive continuum from high-risk stages for psychosis. Microglia and astrocytes establish the link between this immune signalling and the synthesis of noxious tryptophan catabolism products, that cause structural damage and directly hamper normal neurotransmission. Amongst these, only 3-hydroxykynurenine has been consistently described in the blood of FEP patients. CONCLUSION: Peripheral molecules stemming from brain inflammation might provide insightful biomarkers of schizophrenia, as early as FEP or even prodromal phases, although more time- and clinically-adjusted studies are essential for their validation.
Astrocytes ; Biomarkers ; Encephalitis ; Humans ; Interleukin-1 ; Interleukin-4 ; Interleukin-6 ; Interleukin-8 ; Metabolism ; Methods ; Microglia ; Polytetrafluoroethylene ; Psychotic Disorders ; Receptors, Interleukin-2 ; Schizophrenia ; Synaptic Transmission ; Tryptophan

BACKGROUNDVulvovaginal candidiasis is caused by Candida albicans. The vaginal epithelium, as the first site of the initial stage of infection by pathogens, plays an important role in resisting genital tract infections. Moreover, lactobacilli are predominant members of the vaginal microbiota that help to maintain a normal vaginal microenvironment. Therefore, Lactobacillus crispatus was explored for its capacity to intervene in the immune response of vaginal epithelial cells VK2/E6E7 to C. albicans.

METHODSWe examined the interleukin-2 (IL-2), 4, 6, 8, and 17 produced by VK2/E6E7 cells infected with C. albicans and treated with L. crispatus in vitro. The capacity of L. crispatus to adhere to VK2/E6E7 and inhibit C. albicans growth was also tested by scanning electron microscopy (SEM) and adhesion experiments.

RESULTSCompared with group VK2/E6E7 with C. albicans, when treated with L. crispatus, the adhesion of C. albicans to VK2/E6E7 cells decreased significantly by 52.87 ± 1.22%, 47.03 ± 1.35%, and 42.20 ± 1.55% under competition, exclusion, and displacement conditions, respectively. SEM revealed that the invasion of C. albicans into VK2/E6E7 cells was caused by induced endocytosis and active penetration. L. crispatus could effectively protect the cells from the virulence of hyphae and spores of C. albicans and enhance the local immune function of the VK2/E6E7 cells. The concentrations of IL-2, 6, and 17 were upregulated significantly (P < 0.01) and that of IL-8 were downregulated significantly (P < 0.01) in infected VK2/E6E7 cells treated with L. crispatus. The concentration of IL-4 was similar to that of the group VK2/E6E7 with C. albicans (24.10 ± 0.97 vs. 23.12 ± 0.76 pg/ml, P = 0.221).

CONCLUSIONSL. crispatus can attenuate the virulence of C. albicans, modulate the secretion of cytokines and chemokines, and enhance the immune response of VK2/E6E7 cells in vitro. The vaginal mucosa has a potential function in the local immune responses against pathogens that can be promoted by L. crispatus.

Candida albicans ; pathogenicity ; Cell Line, Tumor ; Epithelial Cells ; immunology ; metabolism ; microbiology ; ultrastructure ; Female ; Humans ; Interleukin-17 ; metabolism ; Interleukin-2 ; metabolism ; Interleukin-4 ; metabolism ; Interleukin-6 ; metabolism ; Interleukin-8 ; metabolism ; Lactobacillus crispatus ; physiology ; Microscopy, Electron, Scanning ; Vagina ; cytology

OBJECTIVETo study the role of MEKK2 on the production of IL-2 in Jurkat cells stimulated by PHA/anti-CD28 antibody.

METHODSThe MEKK2 and JNK kinase activities were measured in both dominant negative MEKK2 Jurkat (dnMEKK2 Jurkat) cells and parental Jurkat cells. The AP(1) and IL-2 promotor activities were measured by luciferase activity assay. The IL-2 mRNA and protein were detected by RT-PCR and Western blot.

RESULTSAfter stimulation by PHA/anti-CD28, JNK was activated in parental Jurkat cells but not in dnMEKK2 Jurkat cells. The luciferase report gene activities of AP1 and IL-2 promotors were increased by 4- and 5-folds in parental cells whereas only by 1 fold in dnMEKK2 Jurkat cells. The level of IL-2 mRNA and IL-2 protein were increased in parental Jurkat cells but not in dnMEKK2 Jurkat cells.

CONCLUSIONMEKK2 plays an important role on the production of IL-2 in Jurkat cell stimulated with PHA/anti-CD28 antibody. It is a potential drug target for the treatment of GVHD and autoimmune disease.

Humans ; Interleukin-2 ; biosynthesis ; genetics ; Jurkat Cells ; MAP Kinase Kinase 4 ; metabolism ; MAP Kinase Kinase Kinase 2 ; metabolism ; physiology

OBJECTIVETo investigate the role of integrin α4β7 in the development of ulcerative colitis (UC) in rats.

METHODSSixty Sprague-Dawley rats were randomly divided into the control group (acetone enema), the model group (2,4-dinitrochlorobenzene, DNCB enema), and the α4 intervention group. Colonic mucosa of different groups was observed and compared in terms of pathology and cytokine changes(IL-2 and IL-6) using ELISA. Semi-quantitative RT-PCR was used to detect the colon α4β7 expression. Integrin α4β7(+) lymphocytes in the portal vein of rats were determined by flow cytometry.

RESULTSThe expression of α4 mRNA was 0.68±0.24 in the model group and 0.58±0.37 in the intervention group, and the expression of β7 mRNA was 0.84±0.37 in the model group and 0.65±0.30 in the intervention group, which were all significantly higher as compared to those in the control group(0.15±0.13 for α4 and 0.24±0.62 for β7, P<0.01). The proportions of integrin α4β7 positive lymphocytes in the portal vein in the model group and intervention group were significantly higher than that in the control group [(76.7±8.2)% and (68.2±7.6)% vs. (14.7±6.7)%, P<0.01]. The expression of IL-2 and IL-6 and the result of macroscopic and microscopic scores in the intervention group were lower than those in the model group(P<0.05).

CONCLUSIONSHigh expression of α4β7 may play an important role in experimental colon mucosa inflammation in rats with ulcerative colitis. The blockade of integrin α4β7 may be a potential target to reduce colonic mucosa inflammation.

Animals ; Colitis, Ulcerative ; metabolism ; pathology ; Colon ; metabolism ; pathology ; Disease Models, Animal ; Female ; Integrins ; metabolism ; physiology ; Interleukin-2 ; metabolism ; Interleukin-6 ; metabolism ; Intestinal Mucosa ; pathology ; Rats

ObjectiveTo investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in the rat model of chronic nonbacterial prostatitis (CNP) at different time points of modeling.

METHODSForty adult male SD rats were randomly divided into four groups of equal number, control, 45 d model, 60 d model, and 90 d model, and proteins were obtained from the prostatic tissue of another 30 rats. The CNP model was made by intraperitoneal injection of 0.5 ml DPT vaccineand intradermal injection of mixed solution of 1 ml prostatein extract and complete adjuvant at a 1∶1 ratio, while the control rats were injected with the same volume of normal saline. At 45, 60, and 90 days after modeling, we measured the paw withdrawal threshold (PWT) of the rats, determined the levels of TNF-α, IL-1β, IL-2, and IL-10 in the prostate tissue by ELISA, observed the histomorphological changes in the prostate by transmission electron and light microscopy, and detected the expressions of SP and NK1-R in the L5－S2 spinal cord by immunohistochemistry.

RESULTSThe model rats showed significantly increased sensitivity to pain, with remarkably lowered PWT at 45, 60, and 90 days after modeling. The levels of TNF-α, IL-1β, IL-2, and IL-10 in the prostate tissue were markedly elevated in the CNP models as compared with those in the controls (all P<0.05), most significantly at 90 days (all P<0.05). Immunohistochemistry showed that the expressions of SP and NK-1R were remarkably higher in the CNP model groups than in the control (all P<0.05), the highest at 90 days. Light microscopy revealed no inflammatory cell infiltration in the prostate tissue of the control rats, and obvious edema and increased lymphocytes were observed with the prolonged time of modeling.Transmission electron microscopy showed inflammatory changes in the prostate tissue of the model rats and that peritubular interstitial edema was most obvious at 90 days, with widened intervals between peritubular cells and the epithelial base and increased numbers of fibroblasts and collagen fibrils.

CONCLUSIONSThe synthesis of SP and the level of NK-1R were increased in the posterior horn of the L5－S2 spinal cord in the rat model of CNP.

Animals ; Interleukin-10 ; metabolism ; Interleukin-1beta ; metabolism ; Interleukin-2 ; metabolism ; Male ; Pain ; Prostatitis ; metabolism ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurokinin-1 ; metabolism ; Spinal Cord ; metabolism ; Substance P ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

To explore the effectiveness and safety of a Chinese medicinal decoction Wuwei Xiaodu Drink (WWXDD) in inhibiting chronic osteomyelitis via regulatory T cells signaling. The effective constitutes of WWXDD and osteomyelitis related genes were screened. Target proteins were cross-validated using the Venny database. GO function and KEGG pathway analysis were performed for target proteins, while pharmacological network was constructed. The bone properties were analyzed by HE staining and the concentrations of immune factors were measured by ELISA. The expression of CTLA-4 and Foxp3 mRNA and STAT5, p-STAT5, CTLA-4 and Foxp3 protein were detected using Real-time PCR and Western blot, respectively. FACS was used to analyze the percentages of cells. A total of 117 genes overlapped between 785 target genes of the active compounds of WWXDD and 912 osteomyelitis related genes. Inflammation-related genes, including IL-6, TNFα, IL-1β and IL-2 showed high connection degree in the drug-compound-disease-target network. GO function and KEGG pathway analysis revealed that 117 intersection genes mainly enriched in virus infection related pathways, immune related pathways and chemokine signaling pathway. Furthermore, the development of chronic osteomyelitis was suppressed in model rats after treatment with WWXDD. Meanwhile, the concentrations of IL-2 and CD4⁺CD25⁺Foxp3 Treg percentages together with the levels of p-STAT5, CTLA-4 and Foxp3 were also down-regulated. Furthermore, IL-2 and WWXDD drug-containing serum exhibited opposite effects on regulating IL-2, IL-10, TGF-β1, Foxp3, CTLA4 and STAT5. In addition, a STAT5 phosphorylation inhibitor suppressed the expression of Foxp3 and CTLA-4. WWXDD can treat chronic osteomyelitis through suppressing the main regulating factors of Tregs and interfere its immunodepression. Our results bring a new solution for chronic osteomyelitis.
Animals ; Forkhead Transcription Factors/metabolism* ; Interleukin-2/metabolism* ; Osteomyelitis/metabolism* ; Rats ; STAT5 Transcription Factor/metabolism* ; Signal Transduction ; T-Lymphocytes, Regulatory