Vanadium pentoxide prevents NK-92MI cell proliferation and IFNγ secretion through sustained JAK3 phosphorylation

Vanadium is a major air pollutant with toxic and carcinogenic effects; it also exercises immunosuppressive effects on the adaptive immune response. Its effect on the innate immune response is poorly explored. The aim of this study was to identify if vanadium pentoxide (V₂O₅) impairs the function of immunoregulatory NK cells and to determine possible mechanisms associated with this effect. Interleukin-2-independent NK-92MI cells were exposed to different V₂O₅ concentrations for 6, 12, or 24?h periods. Cell proliferation was then evaluated using CFSE staining, apoptosis by Annexin V binding, and necrosis by 7-AAD staining. The release of IL-2, -4, -6, -10, -17A, IFNγ, and TNFα by the cells were assessed using a human CBA kit. Expression of CD45, SOCS1, JAK3, pJAK3, STAT5, pSTAT5, IL-2R, IL-15R, Fas, and FasL in/on the cells was determined by flow cytometry; JAK3 and pJAK3 expression were also evaluated via confocal microscopy. The results indicated that V₂O₅ could inhibit NK-92MI cell proliferation and induce cell apoptosis in a dose- and time-related manner. V₂O₅ also inhibited IL-2, IL-10, and IFNγ secretion but mostly only after 24?h of exposure and with primarily the higher doses tested. V₂O₅ had no effect on expression of JAK3 and STAT5, but did cause an increase in pJAK3 and appeared to lead (trend) to reductions in levels of phosphorylated STAT5. V₂O₅ increased the expression of IL-2R, IL-15R, Fas, and FasL at concentrations above the 50–100?µM range. V₂O₅ had no effect on expression of the CD45 membrane phosphatase, but it did cause an increase in the expression of SOCS1. These results indicate that a key toxic effect of V₂O₅ on NK cells is a dysregulation of signaling pathways mediated by IL-2. These effects could help to explain the previously-reported deleterious effects on innate immune responses of hosts exposed to inhaled V₂O₅.     

Preactivation with IL-12, IL-15, and IL-18 Induces CD25 and a Functional High-Affinity IL-2 Receptor on Human Cytokine-Induced Memory-like Natural Killer Cells

Natural killer (NK) cells are effector lymphocytes that are under clinical investigation for the adoptive immunotherapy of hematologic malignancies, especially acute myeloid leukemia. Recent work in mice has identified innate memory-like properties of NK cells. Human NK cells also exhibit memory-like properties, and cytokine-induced memory-like (CIML) NK cells are generated via brief preactivation with IL-12, IL-15, and IL-18, which later exhibit enhanced functionality upon restimulation. However, the optimal cytokine receptors and signals for maintenance of enhanced function and homeostasis after preactivation remain unclear. Here, we show that IL-12, IL-15, and IL-18 preactivation induces a rapid and prolonged expression of CD25, resulting in a functional high-affinity IL-2 receptor (IL-2Rαβγ) that confers responsiveness to picomolar concentrations of IL-2. The expression of CD25 correlated with STAT5 phosphorylation in response to picomolar concentrations of IL-2, indicating the presence of a signal-competent IL-2Rαβγ. Furthermore, picomolar concentrations of IL-2 acted synergistically with IL-12 to costimulate IFN-γ production by preactivated NK cells, an effect that was CD25 dependent. Picomolar concentrations of IL-2 also enhanced NK cell proliferation and cytotoxicity via the IL-2Rαβγ. Further, after adoptive transfer into immunodeficient NOD-SCID-γ_c^−/− mice, human cytokine–preactivated NK cells expand preferentially in response to exogenous IL-2. Collectively, these data demonstrate that human CIML NK cells respond to IL-2 via IL-2Rαβγ with enhanced survival and functionality, and they provide additional rationale for immunotherapeutic strategies that include brief cytokine preactivation before adoptive NK cell transfer, followed by low-dose IL-2 therapy.     

Silica nanoparticles as an enhancer in the IL-1β-induced inflammation cycle of A549 cells

Objective: The industrial production and combustion of coal can produce silica nanoparticles (nano-SiO₂). It enters the human body mainly through the respiratory tract and exerts a toxic effect. However, whether nano-SiO₂ can increase the IL-1β-induced inflammatory expression in A549 cells has not been tested. Therefore, the synergistic toxicity of nano-SiO₂ and IL-1β to A549 was observed in our study.

Materials and methods: We exposed A549 cells to nano-SiO₂ (0, 100, 500, and 1000?μg/ml) for 12 and 24?h. The effect of nano-SiO₂ on the viability of A549 cells was observed by the CCK-8 method. The A549 cells were exposed to nano-SiO₂ (1?mg/mL) and cytokine IL-1β (10?ng/mL) for 4?h, and we detected the expression of IL-1β and IL-6 cytokines by real time quantitative polymerase chain (RT-qPCR) and enzyme linked immunosorbent assay (ELISA). The expression of β-Actin, I-κB, phospho-ERK_1/2 (P-ERK_1/2), total-ERK_1/2 (T-ERK_1/2), phospho-JNK (P-JNK), total-JNK (T-JNK), phospho-P38 (P-P38), and total-P38 (T-P38) in A549 cells was detected by the Western Blot method.

Results: The nano-SiO₂ treatment resulted in a time-dependent decrease in the viability of A549 cells. The synergistic effect of nano-SiO₂ and IL-1β was observed on the new production of IL-1β and IL-6 in A549 cells. The Western blot results showed that nano-SiO₂ can increase the expression of IL-1β and IL-6 by promoting the phosphorylation of ERK_1/2 and elevating the phosphorylation of I-κB by IL-1β. IL-1β and IL-6 were induced by nano-SiO₂, and the IL-1β treatment with 20?μM of I-κBα phosphorylation inhibitor (PD98059) and 20?μM of ERK_1/2 inhibitor (BAY11-7082) for 1?h was significantly lower than that of the control group in A549 cells.

Discussion and conclusion: These results indicated that nano-SiO₂ had a toxic effect on A549 cells, and this effect could increase IL-1β on the A549 cell-induced inflammatory response. The results suggested that the release of IL-1β and IL-6 in A549 was enhanced by the synergistic IL-1β-induced phosphorylation of ERK_1/2 and I-κB. This process is similar to a snowball, and it is possible that IL-1β is continuously produced and repeatedly superimposed in A549 cells to produce an inflammatory effect; then, a vicious circle occurs, and an inflammatory storm is accelerated.     

Chinese herbal medicinal ingredients affect secretion of NO,IL-10, ICAM-1 and IL-2 by endothelial cells

Abstract

The aim of this study was to investigate the anti-endotoxin effects of sinomenine, fangchinoline, stachydrine, chuanxionggzine, oxymartrine and evodiamine alkaloids commonly found in Chinese herbal medicines. Porcine endothelial cells were challenged with 1?μg LPS/ml for 3?h and then treated with one of the six alkaloids at three concentrations (1, 5 or 10?μg/ml) for a further 21?h. The supernatants of the cultures were then collected and analyzed for levels of nitric oxide (NO), interleukin (IL)-10, intercellular cell adhesion molecule-1 (ICAM-1) and IL-2 using ELISA kits. The results revealed that sinomenine, stachydrine and chuanxionggzine inhibited production of NO; stachydrine and evodiamine inhibited secretion of IL-10; sinomenine and chuanxionggzine down-regulated ICAM-1 expression; oxymartrine and evodiamine decreased production of IL-2 by the LPS-stimulated endothelial cells. Overall, the data from these studies suggested to us that these six alkaloids might effectively reduce inflammatory responses in situ via changes in the formation of these key regulatory molecules/proteins.     

Oxidative induction of pro-inflammatory cytokine formation by human monocyte-derived macrophages following exposure to manganese in vitro

Abstract

Manganese (as Mn²⁺), a superoxide dismutase mimetic, catalyzes the formation of the relatively stable membrane-permeable reactive oxygen species (ROS) hydrogen peroxide (H₂O₂), a mediator of intracellular redox signaling in immune and inflammatory cells. The goal of this study was to investigate the potential for Mn²⁺, via its pro-oxidative properties, to activate production of pro-inflammatory cytokines/chemokines IL-1β, IL-6, IL-8, IFNγ, TNFα, and G-CSF by human monocyte-derived macrophages in vitro. For these studies, the cells were isolated from peripheral blood mononuclear leukocytes and matured to generate a population of large CD14/CD16 co-expressing cells. The monocyte-derived macrophages were then exposed to bacterial lipopolysaccharide (LPS, 1?μg/ml) or MnCl₂ (25–100?μM)—alone or in combination—for 24?h at 37?°C, after which cell-free supernatants were analyzed using a multiplex cytokine assay procedure. Exposure of the cells to LPS caused modest statistically insignificant increases in cytokine production; MnCl₂ caused dose-related increases in production of all six cytokines (achieving statistical significance of p?<?0.0171–?<?0.0005 for IL-1β, IL-6, IL-8, IFNγ, and TNFα). In the case of LPS and MnCl₂ combinations, the observed increases in production of IL-1β, IL-6, IL-8, IFNγ, and G-CSF were greater than those seen with cells exposed to the individual agents. The Mn²⁺-mediated induction of cytokine production was associated with increased production of H₂O₂ and completely attenuated by inclusion of the H₂O₂-scavenger dithiothreitol, and partially by inhibitors of NF-κB and p38MAP kinase. The findings from the studies here help to further characterize the pro-inflammatory mechanisms that may underpin clinical disorders associated with excess exposure to Mn²⁺, particularly those disorders seen in the central nervous and respiratory systems.     

Effect of IL-15 and Natural Killer Cells on Osteoclasts and Osteoblasts in a Mouse Coculture

This study analyzes the effect of interleukin-15 (IL-15) on osteoclast formation using a coculture of mouse osteoblasts and bone marrow cells (BMCs) stimulated with prostaglandin E2 (PGE₂), which both have important role in rheumatoid arthritis (RA) and periodontal disease (PD). BMCs isolate lacking T (BM^T?) or NK (BM^NK?) cells, BMCs with no cells removed (BM^T+NK+), purified NK cells, and purified T cells were each cocultured with osteoblasts in the presence or absence of PGE₂ and/or IL-15. The number of both osteoclasts and osteoblasts was decreased by IL-15 in a dose-dependent manner in BM^T+NK+, BM^T?. However, the reductions were improved in BM^NK?. The expression of caspase3 in osteoblasts cocultured with NK cells was increased in a dose-dependent manner by IL-15. IL-15 stimulates apoptosis of osteoblasts via activation of NK cells. Since osteoblasts have an important role in bone formation, IL-15 may be an inflammatory bone destructive factor in RA and PD.     

IL-6 release from mouse glia caused by MeHg requires cytosolic phospholipase A2 activation

Methylmercury is a potent neurotoxin that causes severe neurological disorders in fetuses and young children. Recent studies indicated that MeHg could alter levels of immune mediators produced by cells of the central nervous system. Results from this study indicated that MeHg could greatly induce IL-6 release from primary mouse glial cultures. This property was not shared by other cytotoxic heavy metals, such as CdCl₂ or HgCl₂. MeHg was known to induce cytosolic phospholipase A₂ (PLA₂) activation and expression, and this enzyme was required for IL-6 induction in some experimental systems. Further experiments using structurally distinct pharmacological agents were performed to test the hypothesis that MeHg induced PLA₂ activation was necessary for MeHg induced IL-6 release. Results indicated that AACOCF₃ (≥10 μM), MAFP (≥0.625 μM) and BEL (≥0.625 μM) significantly reduced MeHg induced IL-6 release in glia. However, these PLA₂ inhibitors did not block MeHg induced GSH depletion. These results suggested that PLA₂ activation was required for MeHg to induce glial IL-6 release.     

A synthetic hydroxypropenone inhibits nitric oxide,prostaglandin E2, and proinflammatory cytokine synthesis

HMP [3-(2-hydroxyphenyl)-1-(5-methyl-furan-2-y-l) propenone] was evaluated for its ability to inhibit the synthesis of major proinflammatory mediators and cytokines in interferon-γ (IFN-γ)- and lipopolysaccharide (LPS)-induced RAW 264.7 cells and phorbol myristate acetate (PMA)-differentiated/LPS-induced U937 cells. HMP suppressed the production of nitric oxide (NO) with significant inhibitory effects at doses as low as 0.78?μM (P?<?0.05). Prostaglandin E2 (PGE2) secretion was also inhibited at doses of 12.5?μM and above (P?<?0.01). The secretion of both TNF-α and IL-6 were only inhibited at the highest dose used (25?μM; P?<?0.001). IL-1β secretion was also inhibited from 12.5?μM onwards (P?<?0.01). This inhibition was demonstrated to be caused by down-regulation of inducible enzymes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), without direct effect upon iNOS or COX-2 enzyme activity. HMP only inhibited iNOS (P?<?0.001) and IL-1β (P?<?0.05) gene expression at the highest tested concentration. HMP did not affect the secretion of chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) and the anti-inflammatory cytokine IL-10. The most striking effect of HMP was its NO inhibitory activity and therefore we conclude that HMP is a selective inhibitor of iNOS.     

Aerobic training increases the stimulated percentage of CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript> in older men but not older women

The purpose of the present study was to determine whether 12 months of moderate intensity cycling would increase the expression of IL-2 (CD25⁺) receptors in T helper (CD4⁺) lymphocytes in men and women aged 65–75 years. Fourteen men and 10 women completed 52 weeks of moderate intensity cycling (60% VO₂peak). Subjects trained (TR) three times per week for 45 min per session. Eight age-matched untrained (UT) male and eight UT female subjects acted as controls. Resting blood samples were taken from TR and UT subjects every 4 weeks. Leukocyte concentration was measured using a full blood count. PHA-stimulated CD4⁺ lymphocytes were analysed for changes in the expression of CD25⁺, by flow cytometry. Training significantly increased VO_2peak (l min⁻¹, ml kg⁻¹ min⁻¹) in male (+14.3, +16%) and female (+16.7, +27.8%) groups. The TR male group showed a significantly lower percentage of CD4⁺CD25⁺ than the male UT in January but the TR male percentage was significantly higher than the UT male group during February, March, April, May, June, September B and December. The female TR group showed a significantly higher percentage CD4⁺CD25⁺ than the female UT only during July. There were also significant sequential monthly changes in the percentage of CD4⁺CD25⁺ for male and female UT and TR groups. Significant increases in the percentage of CD4⁺CD25⁺ in the male TR group suggest training-enhanced lymphocyte mitogenic responsiveness. Moderate intensity long-term training may increase the recruitment of active memory CD4⁺CD25⁺ in men rather than women.     

Regulation of IL-17A expression in mice following subacute ozone exposure

Exposure to subacute ozone (O₃) causes pulmonary neutrophil recruitment. In mice, this recruitment requires IL-17A. Ozone also causes expression of IL-23 and IL-1, which can induce IL-17A. The purpose of this study was to examine the hypothesis that IL-23 and IL-1 contribute to IL-17A expression and subsequent neutrophil recruitment after subacute O₃ exposure. Wild-type, IL-23^?/?, and Flt3l^?/? mice were exposed to air or 0.3 ppm O₃ for 72 h. Flt3l^?/? mice lack conventional dendritic cells (cDC) that can express IL-23 and IL-1. Other wild-type mice were pre-treated with saline or the IL-1R1 antagonist anakinra prior to O₃ exposure. After exposure, bronchoalveolar lavage (BAL) was performed and lung tissue harvested. The results indicated that pulmonary Il17a mRNA abundance and IL-17A⁺ F4/80⁺ cells were significantly reduced in O₃-exposed IL-23^?/? vs in wild-type mice. In contrast, anakinra had no effect on Il23a or Il17a pulmonary mRNA abundance or on BAL concentrations of the neutrophil survival factor G-CSF, but anakinra did reduce BAL neutrophil numbers, likely because anakinra also reduced BAL IL-6. Compared to air, O₃ caused a significant increase in DC numbers in wild-type, but not in Flt3^?/? mice. However, there was no significant difference in Il23a or Il17a mRNA abundance or in BAL neutrophil count in O₃-exposed Flt3^?/? vs in wild-type mice. From these results, it was concluded that IL-23 but not IL-1 contributes to the IL-17A expression induced by subacute O₃ exposure. Induction of IL-23 by O₃ does not appear to require cDC.     

Chinese herbal medicinal ingredients inhibit secretion of IL-6, IL-8, E-selectin and TXB2 in LPS-induced rat intestinal microvascular endothelial cells

The aim of the research was to investigate the anti-inflammatory mechanism of Pulsatillae Decoction (PD), the levels of interleukin (IL)-6, IL-8, E-selectin, and thromboxane B₂ (TXB₂) secreted by cultured rat intestinal microvascular endothelial cells (RIMECs) were determined after treatment with its active ingredients, namely anemoside B4, anemonin, berberine, jatrorrhizine, palmatine, aesculin, and esculetin. RIMECs were challenged with 1 μg/mL lipopolysaccharide (LPS) for 3?h, and then treated with each of the seven ingredients at three concentrations (1, 5 and 10 μg/mL) for 24?h. The results revealed that anemonin, aesculin and esculetin inhibited the production of IL-6, aesculin and esculetin inhibited the secretion of IL-8, anemoside B4, berberine and jatrorrhizine downregulated E-selectin expression, anemonin, berberine, jatrorrhizine and palmatine decreased the content of TXB₂. All these changes were significant. Taken together, the data suggest that all seven active ingredients of PD can effectively reduce inflammatory response, thus relieving intestinal dysfunction via multiple pathways.     

IL-1β Stimulates the Expression of Prostaglandin Receptor EP4 in Human Chondrocytes by Increasing Production of Prostaglandin E2

Prostaglandin (PG) E₂, which exerts its actions via the PG receptors EP1–4, is produced from arachidonic acid by cyclooxygenase (COX)-1 and COX-2. The aim of this study was to investigate the mechanisms by which interleukin (IL)-1β induces the expression of PG receptors in cultured human chondrocytes and to explore the role of PGE₂ in this process. The cells were cultured with 0, 10, or 100 U/mL IL-1β with or without 1 μM celecoxib, a specific inhibitor of COX-2, for up to 28 days. Expression of the genes encoding COX-1, COX-2, and EP1–4 was quantified using real-time PCR, and expression of the corresponding proteins was examined using immunohistochemical staining. PGE₂ production was determined using ELISA. IL-1β treatment caused a marked dose- and time-dependent increase in the levels of PGE₂, COX-2, and EP4 as compared with the untreated control. It did not affect the expression of COX-1, and it decreased the expression of EP1 and EP2. EP3 expression was not detected in either the absence or the presence of IL-1β. When celecoxib was also present, IL-1β failed to stimulate PGE₂ production and EP4 expression, but its stimulatory effect on COX-2 expression and its inhibitory effect on EP1 and EP2 expression were unchanged. IL-1β increases the production of PGE₂, COX-2, and the PG receptor EP4 in cultured human chondrocytes. The increase in EP4 expression appears to be a result of the increased PGE₂ production.     

Speeding of VO2 kinetics in response to endurance-training in older and young women

The goal of this study was to examine the time-course of changes in oxygen uptake kinetics (??VO_2p) during step-transitions from 20?W to moderate-intensity cycling in response to endurance-training in older (O) and young (Y) women. Six O (69?±?7?years) and 8 Y (25?±?5?years) were tested pre-training, and at 3, 6, 9, and 12?weeks of training. VO_2p was measured breath-by-breath using a mass spectrometer. Changes in deoxygenated-hemoglobin concentration of the vastus lateralis (?[HHb]) were measured by near-infrared spectroscopy in Y (but this was not possible in O). VO_2p and ?[HHb] were modeled with a mono-exponential. Training was performed on a cycle-ergometer three times per week for 45?min at ~70% of VO_2peak. Pre-training ??VO_2p was greater (p?<?0.05) in O (55?±?16?s) than Y (31?±?8?s). After 3?weeks training, ??VO_2p decreased (p?<?0.05) in both O (35?±?12?s) and Y (22?±?4?s). A pre-training ??overshoot?? in the normalized ?[HHb]/VO_2p ratio relative to the subsequent steady-state level (interpreted as a mismatch of local O₂ delivery to muscle VO₂) was observed in Y. Three weeks of training resulted in that ??overshoot?? being abolished. Thus there was a training-induced speeding of VO₂ kinetics in O and Y. In the Y this appeared to be the result of improved matching of local O₂ delivery to muscle VO₂. In O, inadequate systemic O₂ distribution (as indirectly expressed by the arterial-venous O₂ difference/VO_2p ratio) seemed to play a role for the initial slower rate of adjustment in VO_2p.     

Vitamin D decreases expression of NLRP1 and NLRP3 inflammasomes in placental explants from women with preeclampsia cultured with hydrogen peroxide

This study aimed to evaluate the immunomodulatory effect of vitamin D (VD) on the NLRP1 and NLRP3 inflammasomes in placental explants from preeclamptic (PE) and normotensive (NT) pregnant women. Placental explants from eight PE and eight NT pregnant women were cultured with or without hydrogen peroxide (H₂O₂)_, VD or H₂O₂ + VD. Gene and protein expression of NLRP1, NLRP3, HMGB1, caspase-1, IL-1β, TNF-α and IL-18 were determined by qPCR and Western blotting/ELISA. Compared to NT pregnant women, the endogenous gene expression of NLRP1, NLRP3, HMGB1, IL-1β, TNF-α and IL-18 was significantly higher in explants from PE and became decreased after VD treatment. Similarly, VD decreased the protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1β, TNF-α and IL-18 in PE. Placental explants from NT cultured with H₂O₂ showed increased gene and protein expression of NLRP1, NLRP3, caspase-1, IL-1β, TNF-α and HMGB1, while H₂O₂ was also able to increase TNF-α and caspase-1 gene expression in PE. Treatment with H₂O₂ + VD decreased gene/protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1β, TNF-α and IL-18 in PE and NT explants with H₂O₂. NLRP1 and NLRP3 are upregulated in the PE. VD may play an immunomodulatory role in the placental inflammation and downregulates oxidative stress induced in vitro by H₂O_2.     

Low-dose IL-2 induces CD56bright NK regulation of T cells via NKp44 and NKp46

Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (T_regs) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56^bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (T_effs) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-β, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2. The increase in NK cells was also accompanied by an increase in T_reg cells, which is dependent on the presence of CD56^bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.     

Interferon-γ arrests proliferation and causes apoptosis in stromal cell/interleukin-7-dependent normal murine pre-B cell lines and clones in vitro,but does not induce differentiation to surface immunoglobulin-positive B cells

Normal pre-B cells from fetal liver or bone marrow of the mouse proliferate for long periods of time in tissue culture on stromal cells in the presence of interleukin-7 (IL-7). Their IgH loci are partly in germ-line, partly in D_HJ_H-rearranged configuration, while their light chain loci are in germ-line configuration. They express the pre-B cell-specific genes V_preB and λ₅. Proliferation of these pre-B cells is inhibited by interferon (IFN)-γ, with half-maximal inhibition at concentrations between 0.1 and 1 unit/ml. Normal pre-B cells exposed to IFN-γ die by apoptosis, as is evidenced by the disintegration of pre-B cell DNA into oligonucleosomal multimers of 180-200 bp. While the proliferation of pre-B cells from Eμ-bcl-2 transgenic (tg) mice is inhibited by IFN-γ, these cells do not die by apoptosis. IFN-γ does not induce differentiation to more mature B lineage cells. In the absence of IL-7 normal pre-B cells differentiate to V_HD_HJ_H/V_LJ_L-rearranged, surface immunoglobulin-positive B cells expressing the a chain of the IL-2 receptor. They also down-regulate the expression of V_preB and X.5, and lose the capacity to proliferate on stromal cells in the presence of IL-7. In contrast, both normal and Eμ-bcl-2 tg pre-B cells exposed to IFN-γ in the presence of stromal cells and IL-7 fail to differentiate, i.e. do not express surface immunoglobulin, retain expression of V_preB and λ₅, do not express the α chain of the IL-2 receptor, and retain the capacity to proliferate on stromal cells in the presence of IL-7, once IFN-γ is removed. The potential usefulness of a treatment of acute lymphocytic leukemia of the B cell lineage (pre B-ALL) with IFN-γ is discussed.     

Impact of three different types of exercise on components of the inflammatory response

It was hypothesized that muscle injury would be greater with eccentric than with all-out or prolonged exercise, and that immune changes might provide an indication that supplements the information provided by traditional markers such as creatine kinase (CK) or delayed-onset muscle soreness. Eight healthy males [mean (SE): age?=?24.9?(2.3) years, maximum oxygen consumption (V˙O_2max)=43.0?(3.1)?ml?·?kg^?1?·?min^?1] were each assigned to four experimental conditions, one at a time, using a randomized-block design: 5?min of cycle ergometer exercise at 90% V˙O_2max (AO), a standard circuit-training routine (CT), 2?h cycle ergometer exercise at 60% V˙O_2max (Long), or remained seated for 5?h. Blood samples were analyzed for CK, natural killer (NK) cell counts (CD3^?/CD16⁺56⁺), cytolytic activity and plasma levels of the cytokines interleukin (IL)-6, IL-10, and tissue necrosis factor α (TNF-α). CK levels were only elevated significantly 72?h following CT. NK cell counts increased significantly during all three types of exercise, but returned to pre-exercise baseline values within 3?h of recovery. Cytolytic activity per NK cell was not significantly modified by any type of exercise. Prolonged exercise induced significant increases in plasma IL-6 and TNF-α. We conclude that the lack of correlation between traditional markers of muscle injury (plasma CK concentrations and muscle soreness rankings) and immune markers of the inflammatory response suggests that, for the types and intensities of exercise examined in this study, the exercise-induced inflammatory response is modified by humoral and cardiovascular correlates of exercise.