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PubMed2002

IL-12 induces monocyte IL-18 binding protein expression via IFN-gamma.

IL-18 is a Th1 cytokine that synergizes with IL-12 and IL-2 in the stimulation of lymphocyte IFN-gamma production. IL-18 binding protein (IL-18BP) is a recently discovered inhibitor of IL-18 that is distinct from the IL-1 and IL-18 receptor families. In this report we show that IL-18BPa, the IL-18BP isoform with the highest affinity for IL-18, was strongly induced by IL-12 in human PBMC. Other Th1 cytokines, including IFN-gamma, IL-2, IL-15, and IL-18, were also capable of augmenting IL-18BPa expression. In contrast, IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma-inducible protein-10, and Th2 cytokines such as IL-4 and IL-10 did not induce IL-18BPa. Although monocytes were found to be the primary source of IL-18BPa, the induction of IL-18BPa by IL-12 was mediated through IFN-gamma derived predominantly from NK cells. IL-18BPa production was observed in cancer patients receiving recombinant human IL-12 and correlated with the magnitude of IFN-gamma production. The IFN-gamma/IL-18BPa negative feedback loop identified in this study may be capable of broadly controlling immune activation by cytokines that synergize with IL-18 to induce IFN-gamma and probably plays a key role in the modulation of both innate and adaptive immunity.

Antibodies↗

PubMed2006

Role of A1 adenosine receptor in the regulation of coronary flow.

To determine whether A1 adenosine receptors (AR) participate in adenosine-induced changes of coronary flow, isolated hearts from A1AR(-/-) and A1AR(+/+) mice were perfused under constant pressure, and the effects of nonselective and selective agonists were examined. Adenosine, 5'-N-ethylcarboxamidoadenosine (NECA, nonselective), and the selective A2AAR agonist 2-2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) augmented maximal coronary vasodilation in A1AR(-/-) hearts compared with A1AR(+/+) hearts. Basal coronary flow was increased (P < 0.05) in A1AR(-/-) hearts compared with A1AR(+/+) hearts: 2.548 +/- 0.1 vs. 2.059 +/- 0.17 ml/min. In addition, selective activation of A1AR with 2-chloro-N6-cyclopentyladenosine (CCPA) at nanomolar concentrations (1-100 nM) did not significantly change coronary flow; at higher concentrations, CCPA increased coronary flow in A1AR(-/-) and A1AR(+/+) hearts. Because deletion of A1AR increased basal coronary flow, it is speculated that this effect is due to removal of an inhibitory influence associated with A1AR. Adenosine and NECA at approximately EC50 (100 and 50 nM, respectively) increased coronary flow in A1AR(+/+) hearts to 177.86 +/- 8.75 and 172.72 +/- 17% of baseline, respectively. In the presence of the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), the adenosine- and NECA-induced increase in coronary flow in A1AR(+/+) hearts was significantly augmented to 216.106 +/- 8.35 and 201.61 +/- 21.89% of normalized baseline values, respectively. The adenosine- and NECA-induced increase in coronary flow in A1AR(-/-) hearts was not altered by DPCPX. These data indicate that A1AR may inhibit or negatively modulate coronary flow mediated by other AR subtypes (A2A and A2B).

Adaptation, Physiological↗

PubMed1990

The influence of carotid body chemoreceptors on expiratory muscle activity.

Respiratory muscle EMG responses to transient, specific carotid body excitation (NaCN, hypoxia) and inhibition (dopamine, hyperoxia) were studied in 7 unanesthetized standing dogs while intact (N = 7) and during bilateral cold block of the vagi (N = 3). In all dogs carotid body excitation augmented the EMG activities of both expiratory muscles (triangularis sterni, TS; transversus abdominis, TA) and the (inspiratory) crural diaphragm (CR); carotid body inhibition significantly reduced phasic EMG activities in all muscles. With vagal blockade the response of the TS to carotid body stimulation was increased; that of the TA was essentially unchanged from the intact state. In all dogs expiratory muscle recruitment in response to carotid body excitation/inhibition could either precede or follow that of the CR. We conclude that in response to specific, transient carotid body excitation or inhibition: (1) Changes in CR, TS and TA EMGs are qualitatively similar. (2) Vagal feedback is strongly inhibitory to TS and excitatory to TA. (3) Changes in expiratory muscle EMGs do not require preceding changes in the CR. Carotid body stimulation contributes significantly to the generation of phasic expiratory activity during eupnea.

Animals↗

PubMed2005

Schema-based learning of adaptable and flexible prey- catching in anurans II. Learning after lesioning.

The previous companion paper describes the initial (seed) schema architecture that gives rise to the observed prey-catching behavior. In this second paper in the series we describe the fundamental adaptive processes required during learning after lesioning. Following bilateral transections of the hypoglossal nerve, anurans lunge toward mealworms with no accompanying tongue or jaw movement. Nevertheless anurans with permanent hypoglossal transections eventually learn to catch their prey by first learning to open their mouth again and then lunging their body further and increasing their head angle. In this paper we present a new learning framework, called schema-based learning (SBL). SBL emphasizes the importance of the current existent structure (schemas), that defines a functioning system, for the incremental and autonomous construction of ever more complex structure to achieve ever more complex levels of functioning. We may rephrase this statement into the language of Schema Theory (Arbib 1992, for a comprehensive review) as the learning of new schemas based on the stock of current schemas. SBL emphasizes a fundamental principle of organization called coherence maximization, that deals with the maximization of congruence between the results of an interaction (external or internal) and the expectations generated for that interaction. A central hypothesis consists of the existence of a hierarchy of predictive internal models (predictive schemas) all over the control center-brain-of the agent. Hence, we will include predictive models in the perceptual, sensorimotor, and motor components of the autonomous agent architecture. We will then show that predictive models are fundamental for structural learning. In particular we will show how a system can learn a new structural component (augment the overall network topology) after being lesioned in order to recover (or even improve) its original functionality. Learning after lesioning is a special case of structural learning but clearly shows that solutions cannot be known/hardwired a priori since it cannot be known, in advance, which substructure is going to break down.

Animals↗

PubMed1989

Effects of gonadectomy and steroids on pituitary gonadotropin secretion in a frog, Rana pipiens.

Secretory dynamics of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured at various times following gonadectomy in adult male grass frogs, Rana pipiens. Plasma levels and in vitro initial secretory rates of both LH and FSH increased significantly within 1 wk and remained elevated for 3-4 wk of castration. Pituitary FSH and LH content were unchanged. However, dissociation between the two gonadotropins (Gth) occurred thereafter: Secretion of FSH remained elevated for 70 days, but those of LH declined to control levels after 30 days. In vitro secretion of Gth from gonadectomized (gonadx) frogs declined progressively over time reaching control levels after 24 h incubation. The results indicate that elevated pituitary secretion contributes to the observed circulating LH and FSH levels in gonadx frogs, and that FSH and LH may be controlled independently. Replacement therapy with 17 beta-estradiol (E2) suppressed post-gonadectomy increases in plasma Gth and in vitro responses to GnRH, whereas 5 alpha-dihydrotestosterone (DHT) had little effect in vivo and augmented GnRH responses in long-term castrates. In vitro, E2 also inhibited, while 48 h of DHT treatment had no effect on GnRH responsiveness of pituitaries from gonadx frogs. The actions of these steroids were opposite to those typically observed in mammals (and birds), and support the hypothesis that E2 may contribute to seasonal testicular regression in ranid frogs.

Androgens↗

PubMed1978

Evidence for H2-receptor-mediated feed-back regulation of histamine release from endocrine cells in the rat stomach.

1. Pentagastrin reduces the concentration of gastric mucosal histamine in the rat. This effect is counteracted by large doses of histamine H2-receptor agonists which are particularly effective if infused I.V. 2. After blockade of histamine H2-receptors but not of H1-receptors, the pentagastrin-induced reduction of mucosal histamine is greatly augmented and H2-receptor agonists no longer inhibit the response to pentagastrin. 3. It is suggested that in the rat stomach, H2-receptors occur on the histamine storing endocrine cells as well as on parietal cells and that mobilized mucosal histamine inhibits further release of histamine by way of H2-receptor-mediated auto feed-back.

Animals↗

PubMedDate not supplied

Inhibitory effect of dopamine on acetylcholine release from caudate nucleus.

It has been shown that dopamine inhibits the release of acetylcholine (ACh) from nerve terminals of caudate cholinergic interneurons, and the imbalance between dopaminergic and cholinergic system by 6-hydroxydopamine pretreatment leads to an increased ACh release. The Parkinson-syndrome induced by drugs which depress dopaminergic function either by reducing the output of dopamine, such as reserpine, or by antagonizing its action on DA receptors, as for instance haloperidol or chlorpromazine, can be attributed to the augmented release of ACh from caudate cholinergic nerve terminals and a consequent increase of cholinergic outflow from caudate nucleus. However, athetoid and choreiform hyperkinesis in patients and hypermotility in animals might result from increased dopaminergic outflow of nigro-striatal pathway and a consequent reduction in cholinergic neurosecretion of caudate nucleus.

Acetylcholine↗

PubMed1991

Follicle-stimulating hormone increases concentrations of messenger ribonucleic acid encoding cytochrome P450 cholesterol side-chain cleavage enzyme in primary cultures of porcine granulosa cells.

FSH is the primary hormonal inducer of ovarian follicle maturation and a critically important regulator of steroidogenesis in granulosa cells. We examined possible molecular mechanisms subserving FSH action by assessing concentrations of cytochrome P450 cholesterol side-chain cleavage (P450scc) mRNA in porcine granulosa cells maintained in serum-free culture. Cellular concentrations of specific P450scc mRNA were measured by Northern blot hybridization using a 32P-labeled 1-kilobase porcine cDNA clone. Specificity was tested by estimating the granulosa cell mRNA content of the constitutively expressed enzyme, glyceraldehyde-3-phosphate dehydrogenase. Steroidogenesis was evaluated by measuring concomitant progesterone accumulation in the culture medium. Treatment with ovine FSH (100 ng/ml) increased P450scc mRNA concentrations in a time-dependent fashion, with significant effects on both P450scc mRNA concentrations and progesterone accumulation by 4 h and a maximal increase (8- to 10-fold) at 48 h. FSH dose-response studies at 48 h revealed a significant stimulatory effect of 30 ng/ml FSH on P450scc mRNA accumulation and progesterone production, with a maximal effect at 100 ng/ml FSH. To examine the role of cAMP in mediating granulosa cell P450scc mRNA accumulation, granulosa cells were treated with forskolin, cholera toxin, 8-bromo-cAMP, 8-bromo-cGMP, 5'AMP, or cAMP analogs that differentially stimulate the two isoenzymes of protein kinase-A. Increased specific P450scc mRNA accumulation and progesterone production occurred in response to each agent except 5'AMP and 8-bromo-cGMP. No effects of these agents were observed on glyceraldehyde-3-phosphate dehydrogenase mRNA. To assess possible feedback effects of steroid or sterol on FSH-stimulated P450scc mRNA concentrations, granulosa cells were treated with aminoglutethimide to block or with low density lipoprotein to stimulate steroid production. Inhibition of sterol utilization by the cholesterol side-chain cleavage enzyme had no effect on basal or FSH-stimulated concentrations of P450scc mRNA, but markedly suppressed progesterone production. Low density lipoprotein, which increases intracellular sterol, also did not alter basal or FSH-stimulated P450scc mRNA accumulation, suggesting that neither the utilization nor the availability of sterol regulates specific P450scc mRNA levels. Estradiol alone did not increase P450scc mRNA accumulation, but did augment progesterone production. Treatment of granulosa cells with estradiol and FSH produced a synergistic increase in progesterone concentrations, but did not affect FSH-stimulated P450scc mRNA accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

A cascade model for restenosis. A special case of atherosclerosis progression.

BACKGROUND: Restenosis presently limits the long-term success of percutaneous transluminal coronary angioplasty (PTCA) and allied treatments of atheroma. Current views of the pathophysiology of restenosis fail to explain certain important clinical features: Thrombosis, often invoked as a cause of smooth muscle proliferation, wanes before intimal thickening peaks. Prolonged antithrombotic therapy does not eliminate restenosis after PTCA. Furthermore, only a minority of angioplastied lesions develop clinically significant restenosis. METHODS AND RESULTS: We propose a cytokine-growth factor cascade mechanism of restenosis pathobiology that could explain these features of human restenosis. According to this model, PTCA would produce acute local thrombosis and/or mechanical injury that triggers cytokine/growth factor gene expression by resident macrophages and smooth muscle cells. This early acute generation of cytokines could evoke a secondary growth factor and cytokine response that might establish a positive, self-stimulatory autocrine and paracrine feedback loop that would serve to amplify and sustain the proliferative response. This multistage schema would account for the lag between injury and restenosis and the failure of chronic antithrombotic therapy to prevent this process. Human atheromata contain variable numbers of macrophages. The macrophage content of a particular lesion could determine in part propensity to develop restenosis after angioplasty, explaining why all lesions do not develop this process. CONCLUSIONS: Several experimental observations support this novel mechanistic model. Leukocytes and smooth muscle cells express genes for cytokines and growth factors, and products of coagulation and thrombosis can activate mononuclear phagocytes. Cytokines and growth factors often augment their own gene expression and induce one another, providing a potential intralesional amplification loop. Experimental atheroma and advanced human atherosclerotic lesions do not express high levels of growth-stimulatory cytokines such as interleukin-1 or tumor necrosis factor in the basal state but exhibit inducible expression in response to an injurious stimulus. Thus, cascades of autocrine or paracrine mediators whose expression is triggered by vascular injury might contribute to deranged smooth muscle behavior during restenosis.

Angioplasty, Balloon, Coronary↗

PubMed1989

Functional consequences of monocyte IL-2 receptor expression. Induction of IL-1 beta secretion by IFN gamma and IL-2.

The generation of an immune response involves the interaction of monocytes and T cells, but the events which regulate this interaction are not well understood. Culture of human peripheral blood monocytes in vitro induces low level surface expression of the p55 protein of the IL-2R and the expression of this receptor can be enhanced significantly by exposure to IFN-gamma. The addition of IL-2 to IFN-gamma-treated monocytes was shown to augment subsequent IL-1 beta secretion in the presence or absence of LPS. These effects could be partially blocked by anti-p55-IL-2R mAb. Nuclear "run on" assays and Northern analysis to probe for IL-1 beta transcripts showed enhanced IL-1 beta gene transcription and mRNA accumulation by monocytes treated with IFN-gamma and IL-2 but not in cultures that were obtained from monocytes treated with IL-2 alone. These results suggest that the T cell lymphokines IFN-gamma and IL-2 may act in a sequential fashion on monocytes to amplify the immune response by establishing a positive feedback circuit.

Adjuvants, Immunologic↗

PubMed1999

Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells.

We have demonstrated previously that cells from both the skin and peripheral blood from patients with cutaneous T cell lymphoma (CTCL) have elevated levels of protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed levels of Thl cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, IL-12 in vitro can restore IFN-gamma production by these patients' cells to near normal levels. Because retinoids exert therapeutic activity in CTCL and are potent modulators of growth and differentiation of hematopoietic cells, we investigated the role of retinoids in modulating Thl cytokine production. Peripheral blood mononuclear cells (PBMC) from normal donors and patients with CTCL were cultured with medium, IL-2, 13-cis-retinoic acid, all-trans-retinoic acid, acetretin or etretinate alone, or IL-2 plus the retinoids for 24 h, and levels of IFN-gamma were determined using ELISA. IL-2 or retinoids alone could induce low but significant levels of IFN-gamma. However, when IL-2 was cultured with each retinoid, a synergistic augmentation of IFN-gamma levels (4-fold to 90-fold) was observed except in the case of etretinate. All-trans-retinoic acid (ATRA) was the most potent IFN-y inducer. Similar studies performed using PBMC from CTCL patients indicated the IFN-gamma augmentation occurred but in a blunted manner. The IFN-y-inducing effect of ATRA and 13-cis-retinoic acid could be abrogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a role in the synergistic upregulation of IFN-gamma. Using an IL-12 p40-specific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid-treated culture supernatants. Purified monocytes cultured with IL-2 plus ATRA did not secrete IL-12. Only when monocytes were cocultured with lymphocytes was there an increase in IL-12 production, suggesting the involvement of a paracrine feedback loop requiring both monocytes and lymphocytes. These data suggest that retinoids can induce Th1 cytokines from normal and CTCL PBMC and that this induction may be mediated through IL-12 production.

Antigen-Antibody Reactions↗

PubMed1976

Length-induced changes in activation during contraction. A study of mechanical oscillations in strontium-mediated contractions of cat and frog heart muscle.

The plateau phase of prolonged Sr-mediated contractions of preparations of cat and frog heart muscle was used to study the transient response to abrupt changes in load or length. An oscillatory response (total amplitude equal to or less than 5% Lmax) was obtained. Isotonic oscillations were less damped than their isometric counterparts, implying positive feedback and thus a causal role of the perturbation in length. Oscillation frequency was 2-3 HZ at 29 degrees C (Q 10, 2-3); it could be increased by epinephrine or caffeine, independently of their effects on extent of shortening; it otherwise changed as a generally constant function of the length at which the oscillation occurred, whether this was altered by changes in extracellular [Sr], frequency of contraction, or load (independent of the direction and magnitude of the preceding load step). Similar oscillatory responses were induced during Sr- or Ca-mediated contractures. Cat muscles showed an additional slower component to the oscillatory response. Transient augmentation of the velocity-length relationship after abrupt reduction in load, previously described for twitch contractions under certain conditions, appears to be analogous to the first phase of the oscillatory response studied here. Our findings indicate that the oscillation is not attributable to any mechanism intrinsic to myofilament interaction, but rather that it involves length-induced changes in the level of activation, probably mediated by Ca2+ or Sr2+. We conclude that length influences the level of activation during contraction of heart muscle.

Action Potentials↗

PubMed2000

Pituitary-adrenal axis regulation in CRH-deficient mice.

Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.

Adrenalectomy↗

PubMed2005

Developmental activation of calmodulin-dependent facilitation of cerebellar P-type Ca2+ current.

P-type (CaV2.1) Ca2+ channels are a central conduit of neuronal Ca2+ entry, so their Ca2+ feedback regulation promises widespread neurobiological impact. Heterologous expression of recombinant CaV2.1 channels demonstrates that the Ca2+ sensor calmodulin can trigger Ca2+-dependent facilitation (CDF) of channel opening. This facilitation occurs when local Ca2+ influx through individual channels selectively activates the C-terminal lobe of calmodulin. In neurons, however, such calmodulin-mediated processes have yet to be detected, and CDF of native P-type current has thus far appeared different, arguably triggered by other Ca2+ sensing molecules. Here, in cerebellar Purkinje somata abundant with prototypic P-type channels, we find that the C-terminal lobe of calmodulin does produce CDF, and such facilitation augments Ca2+ entry during stimulation by repetitive action-potential and complex-spike waveforms. Beyond recapitulating key features of recombinant channels, these neurons exhibit an additional modulatory dimension: developmental upregulation of CDF during postnatal week 2. This phenomenon reflects increasing somatic expression of CaV2.1 splice variants that manifest CDF and progressive dendritic targeting of variants lacking CDF. Calmodulin-triggered facilitation is thus fundamental to native CaV2.1 and rapidly enhanced during early development.

Animals↗

PubMed1991

Anti-tumor necrosis factor antibody augments edema formation in caerulein-induced acute pancreatitis.

The pathogenesis of acute pancreatitis is incompletely defined, but the outcome is determined in part by an acute inflammatory process. Pancreatitis-associated inflammation appears to play a role in the local retroperitoneal injury as well as in the associated dysfunction of remote organs such as the lung. Tumor necrosis factor (TNF) appears to be a proximal mediator of the inflammatory response. In this study, anti-TNF antibody was administered to rats with caerulein-induced pancreatitis to determine if the observed increases in pancreatic and pulmonary microvascular permeability were related to plasma TNF activity. In contrast to the expected findings, blockade of TNF activity was found to increase the amount of edema formation in both the pulmonary and pancreatic microvascular beds. The mechanism is not known; however, blockade of TNF-induced down regulation of phagocytic cell activity, ablation of TNF-dependent feedback inhibition of other cytokines, failure of induction of endogenous antioxidant systems, or inactivation of the TNF control of microvascular tone are all possible explanations. This is potentially an important observation as clinical strategies are now being developed to modify the inflammatory response in ways presumed advantageous to an injured host.

Acute Disease↗

PubMed1991

Effect of oxygenation on breath-by-breath response of the genioglossus muscle during occlusion.

We investigated the effect of different levels of O2 tension (hypoxia, normoxia, and hyperoxia) on the breath-by-breath onset and peak electromyographic (EMG) activity of the genioglossus (GG) muscle during a five-breath end-expiratory tracheal occlusion of 20- to 30-s duration. GG and diaphragmatic (DIA) EMG activity were measured with needle electrodes in eight anesthetized tracheotomized adult cats. In response to occlusion, the increase in the number of animals with GG EMG activity was different during hypoxia, normoxia, and hyperoxia (P = 0.003, Friedman). During hypoxia, eight of eight of the animals had GG EMG activity by the third occluded effort. In contrast, during normoxia, only four of eight and, during hyperoxia, only three of eight animals had GG EMG activity throughout the entire five-breath occlusion. Similarly, at release of the occlusion, more animals had persistent GG EMG activity on the postocclusion breaths during hypoxia than during normoxia or hyperoxia. Breath-by-breath augmentation of peak amplitude of the GG and DIA EMGs on each occluded effort was accentuated during hypoxia (P less than 0.01) and abolished during hyperoxia (P = 0.10). These results suggest that hypoxemia is a major determinant of the rapidity of onset, magnitude, and sustained activity of upper airway muscles during airway occlusion.

Airway Obstruction↗

PubMed2006

IL-27 suppresses CD28-mediated [correction of medicated] IL-2 production through suppressor of cytokine signaling 3.

IL-27 is a novel IL-6/IL-12 family cytokine that not only plays a role in the early regulation of Th1 differentiation, but also exerts an inhibitory effect on immune responses, including the suppression of proinflammatory cytokine production. However, the molecular mechanism by which IL-27 exerts the inhibitory effect remains unclear. In this study we demonstrate that IL-27 inhibits CD28-mediated IL-2 production and that suppressor of cytokine signaling 3 (SOCS3) plays a critical role in the inhibitory effect. Although IL-27 enhanced IFN-gamma production from naive CD4+ T cells stimulated with plate-coated anti-CD3 and anti-CD28 in the presence of IL-12, IL-27 simultaneously inhibited CD28-mediated IL-2 production. Correlated with the inhibition, IL-27 was shown to augment SOCS3 expression. Analyses using various mice lacking a signaling molecule revealed that the inhibition of IL-2 production was dependent on STAT1, but not on STAT3, STAT4, and T-bet, and was highly correlated with the induction of SOCS3 expression. Similar inhibition of CD28-mediated IL-2 production and augmentation of SOCS3 expression by IL-27 were observed in a T cell hybridoma cell line, 2B4. Forced expression of antisense SOCS3 or dominant negative SOCS3 in the T cell line blocked the IL-27-inudced inhibition of CD28-mediated IL-2 production. Furthermore, pretreatment with IL-27 inhibited IL-2-mediated cell proliferation and STAT5 activation, although IL-27 hardly affected the induction level of CD25 expression. These results suggest that IL-27 inhibits CD28-mediated IL-2 production and also IL-2 responses, and that SOCS3, whose expression is induced by IL-27, plays a critical role in the inhibitory effect in a negative feedback mechanism.

Animals↗

PubMed2001

Co-operation of IL-1 and IL-2 on T-cell activation in mononuclear cell cultures.

In search of an optimized anti-cancer immunotherapy, the combination of IL-2 and IL-1 has been tried. In an in-vitro LAK model, this cytokine cocktail seemed to be quite promising. In our in-vitro model of IL-2 induced T-cell activation we have therefore investigated the co-operation of these two potent immunostimulators. Mononuclear cells were stimulated with CD3 activating antibody in the presence of different cytokines and blocking or neutralizing antibodies. Cytokine concentrations were detected in the supernatants with ELISA. Intracellular IFN-gamma and IL-4 in the different T-cell subsets was measured by flow cytometry. IL-1 and IL-1 receptor antagonist (IL-1Ra) were up-regulated by IL-2, this was achieved independently of IL-12 or CD40/CD40L interaction. As a negative feedback mechanism, IL-1beta induced its natural antagonist, IL-1Ra. Both endogenous and exogenous IL-10 suppressed IL-1beta and induced IL-1Ra, thus markedly decreased the amount of functional IL-1. The combination of IL-2 and IL-1beta lead to a mildly increased Interferon-gamma (IFN-gamma) secretion (+20%, p < 0.05), however, this appeared to be the result of an increased IFN-gamma production per secreting cell, rather than of an increased recruitment of non-secreting cells. Similarly, IL-6 was also induced in an additive fashion (+30%, p < 0.05). For both cytokines, this effect could be significantly augmented by neutralizing IL-1Ra. Concentrations of IL-2 induced IL-10 and soluble Fas ligand (sFasL) were not affected by IL-1beta. We were thus able to demonstrate that IL-1 relays its activity through different pathways than IL-2. Furthermore, we could show that the potentially synergistic action of IL-2 and IL-1 was hindered by the simultaneous induction of signficant amounts of IL-1Ra. From the latter findings we conclude that the combination of IL-2 and IL-1 for cytokine-induced anti-tumor activity may not, but a combination of IL-2 and anti-IL-1Ra might prove beneficial.

CD40 Ligand↗