<em>Interleukin</em> (IL)-2 and IL-<em>15</em> are redundant in stimulating T-cell proliferation in vitro. Their precise role in vivo in governing T-cell expansion and T-cell homeostasis is less clear. Each may have distinct functions and regulate distinct aspects of T-cell activation. The functional receptors for IL-2 and IL-<em>15</em> consist of a private alpha-chain, which defines the binding specificity for IL-2 or IL-<em>15</em>, and shared IL-2 receptor beta- and gamma-chains. The gamma-chain is also a critical signaling component of IL-4, IL-7 and IL-9 receptors. Thus, the gamma-chain is called the common gamma or gamma-c. As these receptor subunits can be expressed individually or in various combinations resulting in the formation of receptors with different affinities, distinct signaling capabilities or both, we hypothesized that differential expression of IL-2 and IL-<em>15</em> receptor subunits on cycling T cells in vivo may direct activated T cells to respond to IL-2 or IL-<em>15</em>, thereby regulating the homeostasis of T-cell response in vivo. By observing in vivo T-cell divisions and expression of IL-2 and IL-<em>15</em> receptor subunits, we demonstrate that IL-<em>15</em> is a critical growth factor in initiating T cell divisions in vivo, whereas IL-2 limits continued T-cell expansion via downregulation of the gamma-c expression. Decreased gamma-c expression on cycling T cells reduced sustained Bcl-2 expression and rendered cells susceptible to apoptotic cell death. Our study provides data that IL-2 and IL-<em>15</em> regulate distinct aspects of primary T-cell expansion in vivo.

Cytokines are believed to play an important role in the pathogenesis of systemic lupus erythematosus (SLE). However, for tumour necrosis factor alpha (TNF-alpha) both beneficial and deleterious effects have been reported. To obtain information about the involvement of this cytokine in the pathophysiology of SLE, serum levels of TNF-alpha, the soluble forms of the 55 and 75 kDa tumour necrosis factor receptors (TNF-R55 and TNF-R75), and <em>interleukin</em>-6 (IL-6) were measured by ELISA in nine female patients over a period of 2 yr. Compared to healthy controls, levels of TNF-alpha (median 47 pg/ml, range < <em>15</em>-222 pg/ml), TNF-R55 (median 1.9 ng/ml, range 0.8-10.8 ng/ml), TNF-R75 (median 4.7 ng/ml, range 1.5-<em>15</em> ng/ml) and IL-6 (median 3.5 pg/ml, range < 3.5-52 pg/ml) were significantly elevated in SLE patients (P < 0.0001 vs controls in all cases). There were strong correlations between TNF-alpha and its soluble receptors (P < 0.0001). Moreover, TNF-alpha and both TNF-Rs strongly correlated with clinical and serological parameters of disease activity, such as the European Consensus Lupus Activity Measurement (ECLAM) score, anti-dsDNA antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and anaemia (P < 0.0001 for all comparisons). TNF-alpha and TNF-R75 also correlated with IL-6 (P < 0.0001). However, no correlation between IL-6 and ECLAM was found, and the correlation of IL-6 with anti-dsDNA was relatively weak; in contrast, IL-6 correlated strongly with CRP and ESR (P < 0.0001). Although these data do not allow us ultimately to discriminate between beneficial and deleterious effects of TNF-alpha, they nevertheless suggest a central role for the TNF system in the pathophysiology of SLE.

Immune-inflammatory markers and their correlations were examined in patients with major depression. Plasma concentrations of <em>interleukin</em>-6 (IL-6), soluble IL-6 receptor (sIL-6R), soluble <em>interleukin</em>-2 receptor (sIL-2R), transferrin receptor (TfR), C-reactive protein (CRP), and alpha 1-acid glycoprotein (AGP), as well as the microheterogeneity of AGP, were measured in 49 major depressed patients during an acute phase of the illness and compared with concentrations in <em>15</em> normal control subjects. Plasma concentrations of IL-6, sIL-6, sIL-2R, TfR, CRP, and AGP were significantly higher in major depressed patients than in healthy control subjects. Patients with higher values of AGP microheterogeneity coefficient (AGP-RC>> 1.5) had significantly higher concentrations of AGP, IL-6, and TfR. The correlations between cytokines and acute phase proteins studied point to a significant role of elevated IL-6 secretion in the induction of Type I AGP microheterogeneity changes that are characteristic of some inflammatory conditions.

While the role of cytokines in mediating injury during hind limb skeletal muscle ischemia followed by reperfusion has recently been described, the role of cytokines in myocardial infarction and ischemia/reperfusion have remained relatively unexplored. We hypothesize that cytokines play an important role in the regulation of postischemic myocardial inflammation. This study reports the temporal sequence of proinflammatory cytokine gene expression in postischemic/reperfused myocardium and localizes <em>interleukin</em>-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha)-protein by immunostaining. Rats were subjected to either permanent left anterior descending (LAD) occlusion or to 35 minutes of LAD occlusion followed by reperfusion and sacrificed up to 7 days later. Rat-specific oligonucleotide probes were used to semiquantitatively assess the relative expression of mRNA for TNF-alpha, IL-1 beta, IL-2, IL-6, interferon-gamma (IFN-gamma), and transforming growth factor-beta 1 (TGF-beta 1) utilizing the reverse transcriptase-polymerase chain reaction amplification technique. Increased cardiac mRNA levels for all cytokines except IL-6 and IFN-gamma were measurable within <em>15</em> to 30 minutes of LAD occlusion and increased levels were generally sustained for 3 hours. During early reperfusion, mRNA levels for IL-6 and TGF-beta 1 were significantly reduced compared with permanent LAD occlusion. In both groups, cytokine mRNA levels all returned to baseline levels at 24 hours, while IL-1 beta, TNF-alpha, and TGF-beta 1 mRNA levels again rose significantly at 7 days only in animals with permanent LAD occlusion. Immunostaining for IL-1 beta and TNF-alpha protein revealed two patterns of reactivity: 1) microvascular staining for both IL-1 beta and TNF-alpha protein only in postischemic reperfused myocardium in early post-reperfusion time points; and 2) staining of infiltrating macrophages in healing infarct zones which was most prominent at 7 days after permanent LAD occlusion. These results provide evidence for local expression of cytokine mRNA in postischemic myocardium and suggest that regulation of local cytokine release is altered during the postischemic period.

Inflammation and insulin resistance associated with visceral obesity are important risk factors for the development of type 2 diabetes, atherosclerosis, and the metabolic syndrome. The 12/<em>15</em>-lipoxygenase (12/<em>15</em>-LO) enzyme has been linked to inflammatory changes in blood vessels that precede the development of atherosclerosis. The expression and role of 12/<em>15</em>-LO in adipocytes have not been evaluated. We found that 12/<em>15</em>-LO mRNA was dramatically upregulated in white epididymal adipocytes of high-fat fed mice. 12/<em>15</em>-LO was poorly expressed in 3T3-L1 fibroblasts and was upregulated during differentiation into adipocytes. Interestingly, the saturated fatty acid palmitate, a major component of high fat diets, augmented expression of 12/<em>15</em>-LO in vitro. When 3T3-L1 adipocytes were treated with the 12/<em>15</em>-LO products, 12-hydroxyeicosatetranoic acid (12(S)-HETE) and 12-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), expression of proinflammatory cytokine genes, including tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein 1 (MCP-1), <em>interleukin</em> 6 (IL-6), and IL-12p40, was upregulated whereas anti-inflammatory adiponectin gene expression was downregulated. 12/<em>15</em>-LO products also augmented c-Jun N-terminal kinase 1 (JNK-1) phosphorylation, a known negative regulator of insulin signaling. Consistent with impaired insulin signaling, we found that insulin-stimulated 3T3-L1 adipocytes exhibited decreased IRS-1(Tyr) phosphorylation, increased IRS-1(Ser) phosphorylation, and impaired Akt phosphorylation when treated with 12/<em>15</em>-LO product. Taken together, our data suggest that 12/<em>15</em>-LO products create a proinflammatory state and impair insulin signaling in 3T3-L1 adipocytes. Because 12/<em>15</em>-LO expression is upregulated in visceral adipocytes by high-fat feeding in vivo and also by addition of palmitic acid in vitro, we propose that 12/<em>15</em>-LO plays a role in promoting inflammation and insulin resistance associated with obesity.

OBJECTIVE

Much of what is known about the inflammatory response in the synovial membrane (SM) of patients with osteoarthritis (OA) comes from studies of synovial tissues from end-stage disease. In this study, we sought to better characterize the inflammatory infiltrate in symptomatic patients with early signs of knee OA, and to determine how inflammatory cell populations relate to the pattern of cytokine and degradative enzyme production.

METHODS

Study populations comprised patients with degenerative meniscal tears and early cartilage thinning undergoing arthroscopic procedures (early OA) and patients undergoing total knee replacement for end-stage OA. Quantitative real-time polymerase chain reaction (PCR) was used to measure expression of SM cytokines and enzymes implicated in the pathogenesis of inflammatory arthritis and OA, as well as cell lineage-specific markers. We quantified synovial fluid (SF) cytokines and enzymes by enzyme-linked immunosorbent assay (ELISA) and SM cell populations by immunohistochemistry.

RESULTS

We found increased levels of SF <em>interleukin</em>-<em>15</em> (IL-<em>15</em>) protein in the early knee OA patients when compared to end-stage OA. Both SF IL-<em>15</em> protein and numbers of CD8 cells within SM correlated with matrix metalloproteinase-1 (MMP-1) and three levels. TNF-alpha, IL-6 and IL-21 were also detectable in the SF of the majority of patients, and IL-<em>15</em> levels were associated with IL-6 levels.

CONCLUSIONS

IL-<em>15</em> is elevated in early knee OA, suggesting activation of an innate immune response in the SM. The association of IL-<em>15</em> expression with CD8 transcripts and MMPs implicates this cytokine in OA pathogenesis and as a candidate therapeutic target.

BACKGROUND

Chronic Fatigue Syndrome (CFS) studies from our laboratory and others have described cytokine abnormalities. Other studies reported no difference between CFS and controls. However, methodologies varied widely and few studies measured more than 4 or 5 cytokines. Multiplex technology permits the determination of cytokines for a large panel of cytokines simultaneously with high sensitivity and with only 30 ul of plasma per sample. No widely accepted laboratory test or marker is available for the diagnosis or prognosis of CFS. This study screened plasma factors to identify circulating biomarkers associated with CFS.

METHODS

Cytokines were measured in plasma from female CFS cases and female healthy controls. Multiplex technology provided profiles of 16 plasma factors including the pro -inflammatory cytokines: tumor necrosis factor alpha (TNFalpha), lymphotoxin alpha (LTalpha), <em>interleukin</em> (IL) - IL-Ialpha, IL-1beta, IL-6; TH1 cytokines: interferon gamma (IFNgamma), IL-12p70, IL-2, IL-<em>15</em>; TH2: IL-4, IL-5; TH17 cytokines, IL-17 and IL-23; anti-inflammatory cytokines IL-10, IL-13; the inflammatory mediator and neutrophil attracting chemokine IL-8 (CXCL8). Analysis by receiver operating characteristic (ROC) curve assessed the biomarker potential of each cytokine.

RESULTS

The following cytokines were elevated in CFS compared to controls: LTalpha, IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IL-12. The following cytokines were decreased in CFS: IL-8, IL-13 and IL-<em>15</em>. The following cytokines were not different: TNFalpha, IFNgamma, IL-2, IL-10, IL-23 and IL-17. Applying (ROC) curve analyses, areas under the curves (AUC) for IL-5 (0. 84), LTalpha (0.77), IL-4 (0.77), IL-12 (0.76) indicated good biomarker potential. The AUC of IL-6 (0.73), IL-<em>15</em> (0.73), IL-8 (0.69), IL-13 (0.68) IL-1alpha (0.62), IL-1beta (0.62) showed fair potential as biomarkers.

CONCLUSIONS

Cytokine abnormalities are common in CFS. In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to more indicative of immune activation and inflammation, rather than specific for CFS. As such, they are targets for herapeutic strategies. Newer techniques allow evaluation of large panels of cytokines in a cost effective fashion.

Chinese translation

BACKGROUND

Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood.

OBJECTIVE

To evaluate the host genetic basis for spontaneous resolution of HCV infection.

METHODS

2-stage, genome-wide association study.

METHODS

13 international multicenter study sites.

METHODS

919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence).

METHODS

Frequencies of 792 721 single nucleotide polymorphisms (SNPs).

RESULTS

Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015).

CONCLUSIONS

Epigenetic effects were not studied.

CONCLUSIONS

IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.

<em>Interleukin</em>-2 (IL2) was initially identified from supernatants of activated lymphocytes over 30 years ago. In the ensuing <em>15</em> years, the cDNAs for both IL2 and the three chains of the <em>interleukin</em>-2 receptor (IL2R) were cloned. Subsequently, many of the downstream biochemical pathways activated by the IL2 receptor complex were identified and the structure of IL2 bound to this tripartite receptor complex was solved. Thus, we now have a very good understanding of how each chain contributes to high affinity IL2 binding and signal transduction. In contrast, over the past 30 years the role that IL2 plays in regulating lymphocyte function has involved many surprising twists and turns. For example, IL2 has been shown, paradoxically, to regulate both lymphocyte proliferation and lymphocyte death. In this review, we briefly outline the original findings suggesting a role for IL2 as a T cell growth factor, as well as subsequent studies pointing to its function as an initiator of activation-induced cell death, but then focus on the newly appreciated role for IL2 and IL2R signaling in the development and homeostasis of regulatory T cells.

BACKGROUND

Interleukin 10 (IL-10) exerts anti-inflammatory actions by counteracting many biological effects of interferon gamma (IFN-gamma).

OBJECTIVE

To investigate this in humans, we studied the effects of human recombinant IL-10 administration on IFN-gamma production by patient leucocytes. Furthermore, we assessed the IFN-gamma inducible molecule neopterin and nitrite/nitrate serum levels, which are indicative of endogenous nitric oxide formation.

METHODS

As part of two placebo controlled double blind studies, we analysed patients with chronic active Crohn's disease (CACD) who received either subcutaneous recombinant human IL-10 (n=44) or placebo (n=10) daily for 28 days, and patients with mild to moderate Crohn's disease (MCD) treated with either subcutaneous IL-10 (n=52) or placebo (n=16) daily for 28 days. Neopterin and nitrite/nitrate concentrations were measured in serum, and ex vivo IFN-gamma formation by lipopolysaccharide or phytohaemagglutinin (PHA) stimulated whole blood cells were investigated before, during, and after IL-10 therapy.

RESULTS

In patients with CACD, the highest dose of 20 microg/kg IL-10 caused a significant increase in serum neopterin on days +15 and +29 of therapy compared with pretreatment levels. No changes were observed for nitrite/nitrate levels under either condition. In MCD, treatment with 20 microg/kg IL-10 resulted in a significant increase in PHA induced IFN-gamma production.

CONCLUSIONS

High doses of IL-10 upregulate the production of IFN-gamma and neopterin. This phenomenon may be responsible for the lack of efficacy of high doses of IL-10 in the treatment of CACD and MCD.

Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. We investigated the regulation of these key functions in human blood-derived macrophages. <em>Interleukin</em>-10 (IL-10) induced the phagocytic pathway, including the C-type lectin CD209 and scavenger receptors, resulting in phagocytosis of mycobacteria and oxidized low-density lipoprotein. IL-<em>15</em> induced the vitamin D-dependent antimicrobial pathway and CD209, yet the cells were less phagocytic. The differential regulation of macrophage functional programs was confirmed by analysis of leprosy lesions: the macrophage phagocytosis pathway was prominent in the clinically progressive, multibacillary form of the disease, whereas the vitamin D-dependent antimicrobial pathway predominated in the self-limited form and in patients undergoing reversal reactions from the multibacillary to the self-limited form. These data indicate that macrophage programs for phagocytosis and antimicrobial responses are distinct and differentially regulated in innate immunity to bacterial infections.

Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8+ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8+CD49a+ Trm cells produced interferon-γ, whereas CD8+CD49a- Trm cells produced <em>interleukin</em>-17 (IL-17). In addition, CD8+CD49a+ Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-<em>15</em>, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8+CD49a+ Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8+CD49a- Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8+ Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases.

The ability of single subunit chimeric receptors containing various integrin beta intracellular domains to mimic and/or inhibit endogenous integrin function was examined. Chimeric receptors consisting of the extracellular and transmembrane domains of the small subunit of the human <em>interleukin</em>-2 receptor connected to either the beta 1, beta 3, beta 3B, or beta 5 intracellular domain were transiently expressed in normal human fibroblasts. When expressed at relatively low levels, the beta 3 and beta 5 chimeras mimicked endogenous ligand-occupied integrins and, like the beta 1 chimera (LaFlamme, S. E., S. K. Akiyama, and K. M. Yamada. 1992. J. Cell Biol. 117:437), concentrated with endogenous integrins in focal adhesions and sites of fibronectin fibril formation. In contrast, the chimeric receptor containing the beta 3B intracellular domain (a beta 3 intracellular domain modified by alternative splicing) was expressed diffusely on the cell surface, indicating that alternative splicing can regulate integrin receptor distribution by an intracellular mechanism. Furthermore, when expressed at higher levels, the beta 1 and beta 3 chimeric receptors functioned as dominant negative mutants and inhibited endogenous integrin function in localization to fibronectin fibrils, fibronectin matrix assembly, cell spreading, and cell migration. The beta 5 chimera was a less effective inhibitor, and the beta 3B chimera and the reporter lacking an intracellular domain did not inhibit endogenous integrin function. Comparison of the relative levels of expression of the transfected beta 1 chimera and the endogenous beta 1 subunit indicated that in 10 to <em>15</em> h assays, the beta 1 chimera can inhibit cell spreading when expressed at levels approximately equal to the endogenous beta 1 subunit. Levels of chimeric receptor expression that inhibited cell spreading also inhibited cell migration, whereas lower levels were able to inhibit alpha 5 beta 1 localization to fibrils and matrix assembly. Our results indicate that single subunit chimeric integrins can mimic and/or inhibit endogenous integrin receptor function, presumably by interacting with cytoplasmic components critical for endogenous integrin function. Our results also demonstrate that beta intracellular domains, expressed in this context, display specificity in their abilities to mimic and inhibit endogenous integrin function. Furthermore, the approach that we have used permits the analysis of intracellular domain function in the processes of cell spreading, migration and extracellular matrix assembly independent of effects due to the rest of integrin dimers. This approach should prove valuable in the further analysis of integrin intracellular domain function in these and other integrin-mediated processes requiring the interaction of integrins with cytoplasmic components.

BACKGROUND

A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.

METHODS

Blood was obtained from 43 septic and <em>15</em> non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and <em>interleukin</em>-2 (IL-2) production were quantitated by flow cytometry.

RESULTS

Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).

CONCLUSIONS

In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Mesenchymal stem cells (MSCs) are multipotent precursors present in adult bone marrow, that differentiate into osteoblasts, adipocytes and myoblasts, and play important roles in hematopoiesis. We examined gene expression of these cells by serial analysis of gene expression, and found that collagen I, secreted protein acidic and rich in cysteine (osteonectin), transforming growth factor beta- (TGF-beta) induced, cofilin, galectin-1, laminin-receptor 1, cyclophilin A, and matrix metalloproteinase-2 are among the most abundantly expressed genes. Comparison with a library of CD34(+) cells revealed that MSCs had a larger number of expressed genes in the categories of cell adhesion molecule, extracellular and development. The two types of cells share abundant transcripts of many genes, some of which are highly expressed in myeloid progenitors (thymosin-beta 4 and beta 10, fos and jun). <em>Interleukin</em>-11 (IL-11), IL-<em>15</em>, IL-27 and IL-10R, IL-13R and IL-17R were the most expressed genes among the cytokines and their receptors in MSCs, and various interactions can be predicted with the CD34(+) cells. MSCs express several transcripts for various growth factors and genes suggested to be enriched in stem cells. This study reports the profile of gene expression in MSCs and identifies the important contribution of extracellular protein products, adhesion molecules, cell motility, TGF-beta signaling, growth factor receptors, DNA repair, protein folding, and ubiquination as part of their transcriptome.

<em>Interleukin</em> (IL)-<em>15</em> is a cytokine that acts on a wide range of cell types but is most crucial for the development, homeostasis, and function of a specific group of immune cells that includes CD8 T cells, NK cells, NKT cells, and CD8 alpha alpha intraepithelial lymphocytes. IL-<em>15</em> signals are transmitted through the IL-2/<em>15</em>R beta and common gamma (gamma C) chains; however, it is the delivery of IL-<em>15</em> to these signaling components that is quite unique. As opposed to other cytokines that are secreted, IL-<em>15</em> primarily exists bound to the high affinity IL-<em>15</em>R alpha. When IL-<em>15</em>/IL-<em>15</em>R alpha complexes are shuttled to the cell surface, they can stimulate opposing cells through the beta/gamma C receptor complex. This novel mechanism of IL-<em>15</em> delivery has been called trans-presentation. This review discusses how the theory of trans-presentation came to be, evidence that it is the major mechanism of action, the current understanding of the cell types thought to mediate trans-presentation, and possible alternatives for IL-<em>15</em> delivery.

Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of <em>interleukin</em> (IL)-6, IL-8, IL- 10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-α, monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-<em>15</em>. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors).

Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of the respiratory tract in which macrophages are the predominant inflammatory cell and for which the efficacy of treatment with corticosteroids is controversial. We investigated the effect of dexamethasone on basal and <em>interleukin</em> (IL)-1beta or cigarette smoke media (CSM)-stimulated release of IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) by bronchoalveolar lavage macrophages from cigarette smokers and patients with COPD (n = <em>15</em>). Basal release of IL-8 was approximately fivefold greater in patients with COPD than smokers, whereas GM-CSF was similar for each group. IL-1beta and CSM increased IL-8 and GM-CSF release by macrophages from both smokers and patients with COPD. Dexamethasone did not inhibit basal or stimulated IL-8 release from macrophages from patients with COPD but inhibited release in smokers. In contrast, basal and IL-1beta-stimulated GM-CSF release, but not CSM-stimulated release, was inhibited by dexamethasone. We conclude that the lack of efficacy of corticosteroids in COPD might be due to the relative steroid insensitivity of macrophages in the respiratory tract.

<em>Interleukin</em> <em>15</em> (IL-<em>15</em>) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ(c)). Here we found that in the structure of the IL-<em>15</em>-IL-<em>15</em>Rα-IL-2Rβ-γ(c) quaternary complex, IL-<em>15</em> binds to IL-2Rβ and γ(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ(c) complex, despite their different receptor-binding chemistries. IL-<em>15</em>Rα substantially increased the affinity of IL-<em>15</em> for IL-2Rβ, and this allostery was required for IL-<em>15</em> trans signaling. Consistent with their identical IL-2Rβ-γ(c) dimer geometries, IL-2 and IL-<em>15</em> showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-<em>15</em> and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-<em>15</em>Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-<em>15</em> or IL-2.

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a <em>15</em> cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine <em>interleukin</em>-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

Surgical operations have been shown to cause a variety of immunological disturbances in man both in vivo and in vitro. With few exceptions the overall picture is one of a generalized state of immunodepression in the postoperative period. The implications of these observations are that host defences may be compromised by surgical procedures, thus providing a 'fertile soil' for bacterial invasion and tumour cell metastasis at the very time when risks from invading pathogens and viable tumour cells are maximal. We have studied the effects of surgical operations on the immune system in 35 patients with benign disease. Surgical procedures were classified as either minor (n = <em>15</em>) or major (n = 20). A panel of monoclonal antibodies was used to identify peripheral blood lymphocyte subpopulations and analysis was performed using flow cytometry. Simultaneous estimations of plasma alpha-1 proteinase inhibitor (alpha-1-PI), alpha-2-macroglobulin (alpha-2-M), alpha-2-pregnancy-associated glycoprotein (alpha-2-PAG) and plasma suppressive activity (PSA) on stimulated allogeneic lymphocytes were performed before operation and on postoperative days 1, 3, 7, 17 and 21. Circulating numbers of all lymphocyte subpopulations fell significantly following surgery, except for B lymphocytes which did not change. The magnitude, and duration of the reduction in cell numbers and the subpopulation affected was significantly related to the degree of surgical trauma, and returned to pre-operative values by postoperative day 7. Changes in alpha-1-PI, alpha-2-M, alpha-2-PAG and PSA were also significantly related to the degree of surgical trauma, and these plasma changes persisted longer than the cellular disturbances. Surgical operations induce a reversible depression of cellular immunity which precedes plasma suppressive activity in its return to pre-operative levels. Immunostimulating agents such as interferon and the <em>interleukins</em> deserve evaluation as prophylactic agents pre-operatively.

A critical aim of vaccine-related research is to identify the mechanisms by which memory T cells are formed and maintained over long periods of time. In recent years, we have designed experiments aimed at addressing two key questions: (i) what are the factors that maintain functionally responsive CD8+ memory cells over long periods of time, and (ii) what are the signals during the early stages of infection that drive the differentiation of long-lived CD8+ memory T cells? We have identified a role for CD4+ T cells in the generation of CD8+ T-cell-mediated protection from secondary challenge. While CD4+ T cells appear to play a role in the programme of CD8 memory, we find that they are also required for the long-term maintenance of CD8+ memory T-cell numbers and function. This property is independent of CD40-CD40L interactions, and we propose a role for CD4+ T cells in maintaining the ability of CD8+ memory T cells to respond to <em>interleukin</em>-7 (IL-7) and IL-<em>15</em>. By manipulating both the time course of infection and the timing of antigen presentation to newly recruited CD8+ T cells, we also demonstrate that the programming of effector and memory potential are at least partially distinct processes.

Tumor necrosis factor alpha (TNFalpha) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, <em>interleukin</em>-8 (IL-8). In this study, we investigate the role of TNFalpha-inducible reactive oxygen species (ROS) in IL-8 expression by "monocyte-like" U937 histiocytic lymphoma cells. TNFalpha is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFalpha requires the presence of an inducible nuclear factor-kappaB (NF-kappaB) (Rel A) binding site in the IL-8 promoter. TNFalpha treatment induces a rapid translocation of the 65 kD transcriptional activator NF-kappaB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to <em>15</em> minutes posttreatment) relative to TNFalpha with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-kappaB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-kappaB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFalpha induces a delayed ROS-dependent signalling pathway that is required for NF-kappaB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFalpha signalling.

The function of <em>interleukin</em> <em>15</em> (IL-<em>15</em>) in unmethylated CpG oligodeoxynucleotide (CpG)-induced immune responses remains unknown. Here, in response to CpG, both wild-type and natural killer cell-depleted mice produced IL-12 and became resistant to a lethal dose of Listeria monocytogenes. In contrast, CpG-treated IL-<em>15</em>-deficient mice produced little IL-12 and succumbed to L. monocytogenes. CpG-stimulated conventional dendritic cells (cDCs) were the main producers of both IL-<em>15</em> and IL-12, but cDCs did not produce IL-12 in the absence of plasmacytoid DCs (pDCs). The cDC-derived IL-<em>15</em> induced CD40 expression by cDCs. Interaction between CD40 on cDCs and CD40 ligand on pDCs led to IL-12 production by cDCs. Thus, IL-<em>15</em>-dependent crosstalk between cDCs and pDCs is essential for CpG-induced immune activation.