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The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3-/-) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3-/- mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3-/- macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3-/- mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3-/- mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15.
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IL-15 is a proinflammatory myokine essential for activating NK cells and CD8+ T lymphocytes, and its overexpression has been related to reducing overall survivorship in patients with acute lymphoblastic leukemia (ALL). Physical exercise has been shown to be safe, feasible, and beneficial in hematological cancers. Exercise requires the activation of muscles that secrete cytokines, such as IL-15, causing immune mobilization. The objective was to compare the outcomes of two training routines on IL-15 and survival prognosis in adult patients diagnosed with ALL. A blind randomized clinical study was carried out where twenty-three peripheral blood samples were obtained pre and postexercise intervention from patients categorized into three types of intervention: the resistance exercise group (REG), the cross-training exercise group (CEG), and the control group (CG). Changes in IL-15 levels during the intervention were not significant in any of the groups (CG p = 0.237, REG p = 0.866, and CEG p = 0.678). However, 87.5% of patients who received an exercise intervention achieved remission, while only 21.73% experienced a relapse. There were no deaths during the study. Although IL-15 level adaptation in the REG and the CG performed similarly, the REG induced a better clinical outcome. Resistance exercises may help improve survival prognosis and reduce relapses in patients with ALL.
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AIM: The purpose of the study was to test the effect of ageing, BMI, physical activity and chronic exercise on IL-15 blood concentration by meta-analyses of the literature. METHODS: The search was performed on PubMed/MEDLINE, Web of Science, ProQuest, Embase and Cochrane databases. First meta-analysis compared blood IL-15 of healthy adults across three age groups (<35 years, 35-65 years, and >65 years), considering BMI as confounding factor; the second compared IL-15 levels between physically active and non-physically active individuals (cross-sectional studies); and the third tested the effect of chronic exercise interventions on blood IL-15 levels on participants of any age, sex, and health condition. RESULTS: From 2582 studies retrieved, 67 were selected for the three meta-analyses (age effect: 59; physical activity cross-sectional effect: 5; chronic exercise effect: 14). Older adults had lower blood IL-15 than young and middle-aged adults (5.30 pg/ml [4.76; 5.83]; 7.11 pg/ml [6.33; 7.88]; 7.10 pg/ml [5.55; 8.65], respectively). However, the subgroup of overweight older adults had higher IL-15 than young and middle aged overweight adults; Habitual physical activity did not affect blood IL-15 (standardized mean difference [SMD] 0.61 [-0.65; 1.88], p = 0.34); Chronic exercise reduced blood IL-15 in short-term interventions (<16 weeks) (SMD -0.14 [-0.27; -0.01], p = 0.04), but not studies of >16 weeks of intervention (SMD 0.44 [-0.26; 1.15], p = 0.22). CONCLUSION: The present meta-analyses highlight the complex interaction of age, BMI and physical activity on blood IL-15 and emphasize the need to take these factors into account when considering the role of this myokine in health throughout life.
Assuntos
Interleucina-15 , Sobrepeso , Idoso , Envelhecimento , Índice de Massa Corporal , Estudos Transversais , Exercício Físico , Humanos , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
OBJECTIVE: To determine if higher levels of circulating interleukin (IL)-15 are positively associated with improvement in insulin resistance in postmenopausal women (PW) with metabolic syndrome (MS). METHODS: According to the median value of IL-15 at baseline, PW older than or equal to 45 years were divided into two groups: higher (n = 43) and lower (n = 42) IL-15. There was a 9-month follow-up period with clinical assessments at baseline and at 9 months (criteria of metabolic syndrome, body fat, and insulin resistance). Insulin resistance (IR) was calculated according to the Homeostasis Model Assessment-estimated insulin resistance (HOMA-IR). For IL-1ß, IL-6, IL-10, IL-13, IL-33, IL-15, and TNF-α was determined using immunoassay Magnetic Bead Panel. RESULTS: There was an interaction between the time and group only for insulin (p = .008) and HOMA-IR (p = .024). After adjusting for confounding variables (clinical and ILs), the HOMA-IR (p = .006) and insulin (p = .003) were lower in the higher-IL-15 group [HOMA-IR: 2.2 (95% CI: 1.9-2.5) and insulin: 9.1 µIU/mL (95% CI: 7.9-10.3)] when compared to the lower-IL-15 group [HOMA-IR: 3.1 (95% CI: 2.6-3.6) and insulin: 12.9 (95% CI: 11.1-14.9)] after 9 months of follow-up. CONCLUSION: Higher levels of circulating IL-15 are positively associated with improvements in IR in PW with MS.
Higher levels of circulating interleukin (IL)-15 are positively associated with improvement in insulin resistance (IR) in postmenopausal women (PW) with metabolic syndrome (MS).This relationship is independent of levels of other cytokines (IL-1ß, IL-6, IL-10, IL-13, IL-33, and TNF-α).The levels of circulating IL-15 may be used as a prognostic biomarker for IR in PW with MS.The study opens the door for future studies on IL-15's role in treating IR among PW with MS.
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Resistência à Insulina , Síndrome Metabólica , Feminino , Humanos , Insulina , Interleucina-10 , Interleucina-13 , Interleucina-15 , Interleucina-33 , Interleucina-6 , Síndrome Metabólica/metabolismo , Pós-Menopausa , Fator de Necrose Tumoral alfaRESUMO
AIMS: This study aimed to evaluate the impact of a 12-week calorie-restricted diet and recreational sports training on gene expressions IL-15, ATROGIN-1 and MURF-1 in skeletal muscle of T2D patients. METHODS: Older adults with T2D (n = 39, 60 ± 6.0 years, BMI 33.5 ± 0.6 kg/m2) were randomly allocated to Diet+Soccer (DS), Diet+Running (DR) or Diet (D). The training sessions were moderate-to-high-intensity and performed 3 × 40 min/week for 12-weeks. Gene expression from vastus lateralis muscle obtained by qRT-PCR, dual-energy X-ray and fasting blood testing measurements were performed before and after 12-weeks. Statistical analysis adopted were two-way ANOVA and Paired t-test for gene expression, and RM-ANOVA test for the remainder variables. RESULTS: Total body weight was reduced in ~4 kg representing body fat mass in all groups after 12-weeks (P < 0.05). HbA1c values decreased in all groups post-intervention. Lipids profile improved in the training groups (P < 0.05) after 12-weeks. ATROGIN-1 and MURF-1 mRNA reduced in the DS (1.084 ± 0.14 vs. 0.754 ± 1.14 and 1.175 ± 0.34 vs. 0.693 ± 0.12, respectively; P < 0.05), while IL-15 mRNA increased in the DR (1.056 ± 0.12 vs. 1.308 ± 0.13; P < 0.05) after 12-weeks intervention. CONCLUSION: Recreational training with a moderate calorie-restricted diet can downregulates the expression of atrophy-associated myokines and increases the expression of anti-inflammatory gene IL-15.
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Restrição Calórica , Diabetes Mellitus Tipo 2 , Exercício Físico , Músculo Esquelético , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Exercício Físico/fisiologia , Expressão Gênica , Humanos , Interleucina-15/biossíntese , Interleucina-15/genética , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Ligases SKP Culina F-Box/biossíntese , Proteínas Ligases SKP Culina F-Box/genética , Proteínas com Motivo Tripartido/biossíntese , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitina-Proteína Ligases/genéticaRESUMO
Paracoccidioidomycosis (PCM) is a systemic fungal disease caused by Paracoccidioides spp., whose clinical outcome depends on immune response. Interleukin 32 (IL-32) is a cytokine present in inflammatory and infectious diseases, including bacterial, virus and protozoan infections. Its role in fungal disease remains unclear. The axis IL-15, IL-32 and vitamin D leads to microbicidal capacity against intracellular pathogens. Thus, the aims of this study were to investigate the production of IL-32 during Paracoccidioides spp. infection and whether this cytokine and IL-15 can increase P. brasiliensis control in a vitamin D dependent manner. IL-32 was highly detected in oral lesions from patients with PCM. In addition, high production of this cytokine was intracellularly detected in peripheral blood mononuclear cells (PBMCs) from healthy donors after exposure to particulated P. brasiliensis antigens (PbAg). The IL-32γ isoform was predominantly expressed, but there was mRNA alternative splicing for IL-32α isoform. The induction of IL-32 was dependent on Dectin-1 receptor. Infection of PBMCs with P. brasiliensis yeasts did not significantly induce IL-32 production even after activation with exogenous IFN-γ or IL-15 treatments. Although IL-15 was a potent inducer of IL-32 production, treatment with this cytokine did not increase the fungal control unless vitamin D was present in high levels. In this case, both IL-15 and IL-32 increased fungicidal activity of PBMCs. Together, data showed that IL-32 is present in lesions of PCM, PbAg induces IL-32, and the axis of IL-15/IL-32/vitamin D can contribute to control fungal infection. The data suggest that exposure to molecules from P. brasiliensis, as ß-glucans, is needed to induce IL-32 production since only heat-killed and sonicated P. brasiliensis yeasts were able to increase IL-32, which was blocked by anti-Dectin-1 antibodies. This is the first description about IL-15/IL-32/vitamin D pathway role in P. brasiliensis infection.
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Paracoccidioides , Paracoccidioidomicose , Humanos , Interleucina-15 , Interleucinas , Leucócitos Mononucleares , Vitamina DRESUMO
Interleukin (IL)-15 plays an important role in several inflammatory diseases. We have previously identified an IL-15 antagonist called P8 peptide, which binds specifically to IL-15 receptor alpha subunit. However, the P8 peptide rapidly degraded by proteases, limiting its therapeutic application. Thus, we replaced each P8 peptide l-amino acid by its corresponding d-isomers. First, we determined the biological activity of the resulting peptides in a proliferation assay by using CTLL-2 cells. The substitution of l-Ala by d-Ala ([A4a]P8 peptide) increased the inhibitory effect of the P8 peptide in CTLL-2 cells in five-fold. In addition to that, the [A4a]P8 peptide dimer showed the most inhibitory effect. To protect the [A4a]P8 peptide and its dimer against exopeptidase activity, we acetylated the N-terminal of these peptides. At least a three-fold reduction in antagonist activity of acetylated peptides was exhibited. However, the substitution of the N-terminal l-Lys residue of [A4a]P8 peptide and its dimer by d-Lys ([K1k;A4a]P8 peptide) did not affect the antagonist effect of the aforementioned peptides. The [K1k;A4a]P8 peptide dimer was stable to the degradation of trypsin, chymotrypsin, and pepsin up until 48 min. Also, the safety and immunogenicity studies in healthy BALB/c mice demonstrated that the administration of this peptide did not affect the clinical parameters of the animals nor generated antipeptide antibodies. Our findings reveal that two distinct d-amino acid substitutions and dimerization increase the biological activity and stability of P8 peptide. The resulting peptide constitutes a novel IL-15 antagonist with potential applicability in inflammatory diseases.
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Interleucina-15/antagonistas & inibidores , Peptídeos/farmacologia , Substituição de Aminoácidos/efeitos dos fármacos , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Dimerização , Feminino , Interleucina-15/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/síntese química , Peptídeos/químicaRESUMO
IL-15 is part of the immune response in pulmonary tuberculosis (PTB) but amazingly, it may also induce physiological effects similar to those of insulin. We evaluated the IL-15 and insulin plasmatic levels in adults with PTB and with or without type 2 diabetes mellitus (DM2), who received previous antituberculosis therapy for at least 2 months. We analyzed the concentrations of glucose, glycated hemoglobin, insulin, as well as levels of IL-15, IL-2, IFN-γ, and TNF-α in patients with PTB, patients with PTB-DM2, household contacts with DM2 (C-DM2), and healthy household contacts (H-C). Our results showed unexpected high levels of glucose, insulin, and IL-15 in the PTB and C-DM2 groups. In comparison, low levels of these same indicators were observed in the PTB-DM2 and H-C groups. Interestingly, our analysis showed a positive correlation of IL-15 with insulin in the PTB group (râ¯=â¯0.73) and in the C-DM2 group (râ¯=â¯0.66). In comparison, a weak correlation between IL-15 and insulin was observed in the PTB-DM group (râ¯=â¯0.10) and in the H-C group (ρâ¯=â¯0.26). Our results suggest an association between IL-15 and insulin levels in the patient with PTB. Intriguingly, this association was weaker in the patient with PTB-DM2.
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Diabetes Mellitus Tipo 2/sangue , Insulina/sangue , Interleucina-15/sangue , Tuberculose Pulmonar/sangue , Adulto , Idoso , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Interleukin (IL)-15 is an inflammatory cytokine that constitutes a validated therapeutic target in some immunopathologies, including rheumatoid arthritis (RA). Previously, we identified an IL-15 antagonist peptide named [K6T]P8, with potential therapeutic application in RA. In the current work, the metabolic stability of this peptide in synovial fluids from RA patients was studied. Moreover, [K6T]P8 peptide was labeled with 99m Tc to investigate its stability in human plasma and its biodistribution pattern in healthy rats. The biological activity of [K6T]P8 peptide and its dimer was evaluated in CTLL-2 cells, using 3 different additives to improve the solubility of these peptides. The half-life of [K6T]P8 in human synovial fluid was 5.88 ± 1.73 minutes, and the major chemical modifications included peptide dimerization, cysteinylation, and methionine oxidation. Radiolabeling of [K6T]P8 with 99m Tc showed a yield of approximately 99.8%. The 99m Tc-labeled peptide was stable in a 30-fold molar excess of cysteine and in human plasma, displaying a low affinity to plasma proteins. Preliminary biodistribution studies in healthy Wistar rats suggested a slow elimination of the peptide through the renal and hepatic pathways. Although citric acid, sucrose, and Tween 80 enhanced the solubility of [K6T]P8 peptide and its dimer, only the sucrose did not interfere with the in vitro proliferation assay used to assess their biological activity. The results here presented, reinforce nonclinical characterization of the [K6T]P8 peptide, a potential agent for the treatment of RA and other diseases associated with IL-15 overexpression.
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Artrite Reumatoide/sangue , Interleucina-15/antagonistas & inibidores , Peptídeos/síntese química , Tecnécio/química , Animais , Linhagem Celular , Humanos , Técnicas In Vitro , Camundongos , Peptídeos/química , Peptídeos/farmacocinética , Estabilidade Proteica , Ratos , Ratos Wistar , Líquido Sinovial/química , Distribuição TecidualRESUMO
Interleukin IL-15 (IL-15) has been implicated in the development of coronary artery disease (CAD). The aim of the present study was to evaluate the role of IL-15 gene polymorphisms as susceptibility markers for development of subclinical atherosclerosis (SA) and cardiovascular risk factors in Mexican population. Four IL-15 gene polymorphisms (rs4956403, rs3806798, rs1057972 and rs10833) were analyzed in a group of 397 individuals with SA and 1120 controls. Under different inheritance models adjusted by traditional risk factors, the rs10833T allele was associated with increased risk of developing SA [OR=1.42, Pcodom1=0.046; OR=1.48, Pdom=0.021; OR=1.43, Padd=0.014]. Under a dominant model, the rs1057972 polymorphism was associated with central obesity (P=0.045) and fatty liver (P=0.021), while the rs10833 polymorphism was associated with metabolic syndrome (P=0.007) in individuals with SA. The TAC haplotype was significantly associated with a decreased risk of SA. Individuals with rs10833CC genotype exhibited higher levels of IL-15 than individuals with CT+TT genotypes. The results suggest that IL-15 polymorphisms are involved in the risk of developing SA and are associated with metabolic syndrome, central obesity and fatty liver in our study population. The rs10833 polymorphism could be involved in regulating IL-15 production in SA.
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Aterosclerose/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Interleucina-15/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Demografia , Feminino , Haplótipos/genética , Humanos , Masculino , México , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Recombinant simian IL-15 (siIL-15) was obtained for the preclinical assessment of an anti-human IL-15 vaccine. For this purpose, the cDNA from peripheral blood mononuclear cells of a Macaca fascicularis monkey was cloned into a pIL-2 vector. The siIL-15 was expressed in Escherichia coli strain W3110 as an insoluble protein which accounted for 13% of the total cellular proteins. Inclusion bodies were solubilized in an 8 M urea solution, which was purified by ion exchange and reverse phase chromatography up to 92% purity. The protein identity was validated by electrospray ionization-mass spectrometry, confirming the presence of the amino acids which distinguish the siIL-15 from human IL-15. The purified siIL-15 stimulates the proliferation of cytotoxic T-lymphocytes line (CTLL)-2 and Kit 225 cells with EC50 values of 3.1 and 32.5 ng/mL, respectively. Antisera from modified human IL-15-immunized macaques were reactive to human and simian IL-15 in enzyme-linked immunosorbent assays. Moreover, the anti-human IL-15 antibodies from immune sera inhibited siIL-15 activity in CTLL-2 and Kit 225 cells, supporting the activity and purity of recombinant siIL-15. These results indicate that the recombinant siIL-15 is biologically active in two IL-15-dependent cell lines, and it is also suitable for the preclinical evaluation of an IL-15-based therapeutic vaccine.
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Interleucina-15/genética , Macaca fascicularis/genética , Vacinas Sintéticas/genética , Animais , Linhagem Celular , Clonagem Molecular/métodos , Escherichia coli/genética , Humanos , Interleucina-15/imunologia , Macaca fascicularis/imunologia , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas Sintéticas/imunologiaRESUMO
AIM: To evaluate the ability of interleukin (IL)-15 to control T cell functions through its influence on CD30 and OX40 expressing cells in Celiac Disease (CD). In peripheral blood (PB), by examining the expression of OX40 in conventional effectors cells and T cells with a phenotypic specialization of regulatory cells [CD4+CD25high forkhead box protein 3 (Foxp3)+], and the co stimulation of IFN-γ and IL-4 production within CD30 and OX40 positive subsets of T cells. At the duodenal mucosa, by assessing the expression of CD30 and OX40 in intraepithelial (IE) and lamina propria (LP) lymphocytes (IEL, LPL). PATIENTS AND METHODS: PB and duodenal mucosal biopsies were obtained from 38 patients with classic CD (Cel) and 38 healthy controls (HC). Analysis of cell surface and/or intracellular antigens was performed in anti-CD3-treated PB mononuclear cells (PBMC) before and after treatment with recombinant IL-15 (rIL-15), and in IE and LP cellular suspensions prepared from duodenal biopsies pre-treated with/without rIL-15. RESULTS: A subpopulation of CD3+OX40+ T blasts was induced in Cel and HC by a 3days treatment of PBMC with anti-CD3 and decreased its size thereafter, regardless of the presence of rIL-15. However, the addition of rIL-15 to T blasts distinctively induced the survival of T cells with a regulatory phenotype that expresses OX40 antigen in Cel (p<0.05). Celiac patients showed higher frequencies of IFN-γ-producing CD3+CD30+ blasts before and after treatment with rIL-15 (p<0.05, vs. HC). IL-15 increased the frequencies of CD3+CD30+ LPL (HC: p<0.05, Cel: p<0.05) but not of CD3+OX40+ LPL, and CD30 or OX40 positive IEL. CONCLUSIONS: The distinctive control of OX40+ cells with a T regulatory phenotype mediated by the influence of IL-15 comes out as new function of this cytokine in the context of CD. The higher production of IFN-γ by a subpopulation of peripheral CD3+CD30+ cells contributes to the type I biased immune response.
Assuntos
Doença Celíaca/imunologia , Interleucina-15/imunologia , Antígeno Ki-1/imunologia , Ligante OX40/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Complexo CD3/imunologia , Duodeno/imunologia , Feminino , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-15/uso terapêutico , Interleucina-4/biossíntese , Interleucina-4/imunologia , Mucosa Intestinal/imunologia , Masculino , Pessoa de Meia-Idade , Mucosa/citologia , Mucosa/imunologia , Proteínas Recombinantes/uso terapêutico , Adulto JovemRESUMO
Interleukin-15 (IL-15) is a pleiotropic cytokine which regulates the proliferation, survival and the secretory activities of many distinct cell types in the body. This cytokine is produced by macrophages and many other cell types in response to infectious agents; it controls growth and differentiation of T and B lymphocytes, activation of Natural Killer (NK) and phagocytic cells, and contributes to the homeostasis of the immune system. The present review focuses on the biological and modulatory effects of IL-15 in microbial infections and shows that this cytokine may play a role in the host defense against infections by inducing activation of effector cells from both innate and adaptive immune system.(AU)
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Citocinas , Interleucina-15 , Sistema Imunitário , Infecções/microbiologia , Produtos Biológicos/imunologiaRESUMO
Interleukin-15 (IL-15) is a pleiotropic cytokine which regulates the proliferation, survival and the secretory activities of many distinct cell types in the body. This cytokine is produced by macrophages and many other cell types in response to infectious agents; it controls growth and differentiation of T and B lymphocytes, activation of Natural Killer (NK) and phagocytic cells, and contributes to the homeostasis of the immune system. The present review focuses on the biological and modulatory effects of IL-15 in microbial infections and shows that this cytokine may play a role in the host defense against infections by inducing activation of effector cells from both innate and adaptive immune system.