Biomedical subjects

M Rubinstein

Publications and source records attributed to M Rubinstein.

At least 37 records · Page 2Linked to original sources

PubMed2001

Counterion phase transitions in dilute polyelectrolyte solutions.

In dilute solutions of rodlike polyelectrolytes some counterions are distributed far from polyions while others are located in their vicinity in the regions of cylindrical symmetry of the electrostatic potential. For these cylindrical regions around rodlike polyelectrolytes we find an exact solution of the nonlinear Poisson-Boltzmann equation for the case of nonzero net charge in these regions. This exact solution implies three qualitatively different phases of counterion distribution around the polyions with second order phase transitions between these phases.

Journal Article↗

PubMed2001

An astroglia-linked dopamine D2-receptor action in prefrontal cortex.

Typical neuroleptic drugs elicit their antipsychotic effects mainly by acting as antagonists at dopamine D2 receptors. Much of this activity is thought to occur in the cerebral cortex, where D2 receptors are found largely in inhibitory GABAergic neurons. Here we confirm this localization at the electron microscopic level, but additionally show that a subset of cortical interneurons with low or undetectable expression of D2 receptor isoforms are surrounded by astrocytic processes that strongly express D2 receptors. Ligand binding of isolated astrocyte preparations indicate that cortical astroglia account for approximately one-third of the total D2 receptor binding sites in the cortex, a proportion that we found conserved among rodent, monkey, and human tissues. Further, we show that the D2 receptor-specific agonist, quinpirole, can induce Ca(2+) elevation in isolated cortical astrocytes in a pharmacologically reversible manner, thus implicating this receptor in the signaling mechanisms by which astrocytes communicate with each other as well as with neurons. The discovery of D2 receptors in astrocytes with a selective anatomical relationship to interneurons represents a neuron/glia substrate for cortical dopamine action in the adult cerebral cortex and a previously unrecognized site of action for antipsychotic drugs with affinities at the D2 receptor.

Animals↗

PubMed2001

The role of the D(2) dopamine receptor (D(2)R) in A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular responses as revealed by A(2A) and D(2) receptor knockout mice.

The A(2A)R is largely coexpressed with D(2)Rs and enkephalin mRNA in the striatum where it modulates dopaminergic activity. Activation of the A(2A)R antagonizes D(2)R-mediated behavioral and neurochemical effects in the basal ganglia through a mechanism that may involve direct A(2A)R-D(2)R interaction. However, whether the D(2)R is required for the A(2A)R to exert its neural function is an open question. In this study, we examined the role of D(2)Rs in A(2A)R-induced behavioral and cellular responses, by using genetic knockout (KO) models (mice deficient in A(2A)Rs or D(2)Rs or both). Behavioral analysis shows that the A(2A)R agonist 2-4-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine reduced spontaneous as well as amphetamine-induced locomotion in both D(2) KO and wild-type mice. Conversely, the nonselective adenosine antagonist caffeine and the A(2A)R antagonist 8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking the D(2)R, although the stimulation was significantly attenuated. At the cellular level, A(2A)R inactivation counteracted the increase in enkephalin expression in striatopallidal neurons caused by D(2)R deficiency. Consistent with the D(2) KO phenotype, A(2A)R inactivation partially reversed both acute D(2)R antagonist (haloperidol)-induced catalepsy and chronic haloperidol-induced enkephalin mRNA expression. Together, these results demonstrate that A(2A)Rs elicit behavioral and cellular responses despite either the genetic deficiency or pharmacological blockade of D(2)Rs. Thus, A(2A)R-mediated neural functions are partially independent of D(2)Rs. Moreover, endogenous adenosine acting at striatal A(2A)Rs may be most accurately viewed as a facilitative modulator of striatal neuronal activity rather than simply as an inhibitory modulator of D(2)R neurotransmission.

Adenosine↗

PubMed2001

Leptin induces angiopoietin-2 expression in adipose tissues.

Adipose tissues consisting of adipocytes, microvasculature, and stroma are completely ablated upon over-expression of leptin in rats. This tissue regression is mediated by enhanced lipid beta-oxidation, adipocyte dedifferentiation, and apoptosis. To further characterize this phenomenon, we studied the possible effect of leptin on the adipose microvasculature. Tissue microvasculature is maintained by the interplay between positive and negative signals mediated by factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, angiopoietin-1 (Ang-1), and Ang-2. Expression of the negative signal Ang-2 was reported in fetal tissues and in the adult ovary, which undergoes vascular remodeling or regression. We demonstrate that leptin induces the expression of Ang-2 in adipose tissue without a concomitant increase in VEGF. Induction of Ang-2 occurred in an autocrine manner, as demonstrated in cultured adipocytes but not in several other cell types. This tissue-specific induction of Ang-2 coincided with initiation of apoptosis in adipose endothelial cells. We propose that induction of Ang-2 by leptin in adipose cells is one of the events leading to adipose tissue regression.

3T3 Cells↗

PubMed2001

Comparative, topographically-based evaluation of behavioural phenotype and specification of D(1)-like:D(2) interactions in a line of incipient congenic mice with D(2) dopamine receptor 'knockout'.

Phenotypes were assessed topographically in mice lacking functional D(2) dopamine receptors ['knockouts'], using an ethologically based approach to assess all behaviours in the natural repertoire. D(2)-null mice evidenced an ethogram characterised initially by modest reductions in locomotion and shifts in rearing topographies. Subsequently, topographies of behaviour habituated similarly for wildtypes and 'knockouts'. Following challenge with the D(2)-like agonist RU 24213, both inhibition of rearing at a lower dose and induction of stereotyped sniffing and ponderous locomotion at higher doses were essentially absent in D(2)-null mice. Following challenge with the D(1)-like agonist A 68930, vacuous chewing was released in D(2)-null mice. This topographical approach to phenotypic characterisation implicates: (i) the D(2) receptor in these D(2)-like agonist effects and in oppositional D(1)-like: D(2)-like interactions; and (ii) the operation of material compensatory processes consequent to the developmental absence of D(2) receptors which are able to maintain ethological function under tonic, 'naturalistic' conditions but not under 'phasic' challenge.

Animals↗

PubMed2001

The D2 receptor is critical in mediating opiate motivation only in opiate-dependent and withdrawn mice.

According to the dual systems model for opiate reward, dopamine mediates opiate motivation when an animal is in a deprived motivational state (i.e. opiate-dependent and in withdrawal) and not when an animal is in a nondeprived state (i.e. previously drug-naive). To determine the role of the D2 dopamine receptor subtype in mediating opiate motivation, we examined the behaviour of N5 congenic D2 receptor knockout mice and their wild-type siblings in opiate-naive and opiate-dependent and withdrawn place conditioning paradigms. Opiate-naive D2 receptor knockout mice demonstrated acquisition of morphine-conditioned place preference but failed to acquire place preference when conditioned in the deprived state. We propose that D2 receptor function is critical in mediating the motivational effects of opiates only when the animal is in an opiate-dependent and withdrawn motivational state. These findings also underscore the important influence of the genetic background to a given phenotype, as evidenced by the observation that increasing the allelic contribution from the 129/SvJ strain abolishes morphine place preference in C57BL/6 wild-type mice.

Animals↗

PubMed2001

Interleukin-18 binding protein in acute graft versus host disease and engraftment following allogeneic peripheral blood stem cell transplants.

Dysregulation of the cytokine network plays an important role in graft-versus-host disease (GVHD). Interleukin-18 (IL-18) is an obligatory cytokine for interferon-gamma (IFN-gamma) production and IFN-gamma and sIFN-gammaR are elevated in patients with GVHD. Because IL-18 binding protein (IL-18BP) is an inhibitor of IL-18-mediated IFN-gamma production, we evaluated IL-18BP levels in patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT). IL-18BP levels were assessed in 14 patients on day -10 (before conditioning), on the day of transplant, on the day of engraftment, and during transplant-related complications. A comparison of the kinetics of IL-18BP and soluble(s) IL-6R, sIFN-gammaR, IL-18 serum levels was performed. IL-18BP levels were assessed by specific monoclonal antibodies in a double-sandwich enzyme-linked immunosorbent assay (ELISA). In all patients IL-18BP levels decreased during conditioning and increased in parallel with engraftment (p < 0.05). Accordingly, during rejection, IL-18BP serum levels remained low and similar to pretransplant levels. The mean elevation of IL-18BP detected in association to acute GVHD was significantly higher in comparison to normal engraftment (p < 0.05). A correlation between IL-18BP, sIFNgammaR, and sIL-6R serum levels was found in all patients. No correlation between IL-18 and IL-18BP serum levels was found in patients undergoing uneventful PBSCT and rejection, whereas a marked increase in both IL-18 and IL-18BP levels was detected during acute GVHD (p < 0.01). Our data suggest that the dysregulation of IL-18 and IL-18BP may be important in the pathophysiology of transplant-related complications. Furthermore, because preliminary data from our group show that IL-18 blockage ameliorates GVHD in murine models, it is inferred that these cytokines may represent potential targets in the development of new therapeutic strategies in acute GVHD.

Acute Disease↗

PubMed2001

Differential roles of interleukin-18 (IL-18) and IL12 for induction of gamma interferon by staphylococcal cell wall components and superantigens.

The roles of endogenous cytokines induced by either intact staphylococcal microorganisms or staphylococcal exotoxins were examined using human whole-blood cultures. To accomplish this, interleukin-18 binding protein (IL-18BP) and tumor necrosis factor binding protein (TNFbp) were used to neutralize IL-18 and TNF, respectively, whereas an anti-IL-12 monoclonal antibody was used to neutralize IL-12 and the IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 receptors. Heat-killed Staphylococcus epidermidis and Staphylococcus aureus, as well as the staphylococcal superantigens toxic shock syndrome toxin-1 (TSST-1) and staphylococcus enterotoxin B (SEB) induced gamma interferon (IFN-gamma) production. Staphylococcus spp.-induced production of IFN-gamma required the presence of endogenous IL-18, IL-12, and TNF. In contrast, TSST-1-induced IFN-gamma was not significantly reduced in the presence of IL-18BP, anti-IL-12 antibodies, IL-1Ra, or anti-TNFbp. SEB-induced IFN-gamma was significantly inhibited only by anti-IL-12 antibodies, indicating that endogenous IL-18, IL-1, and TNF are not required for SEB-induced IFN-gamma. In conclusion, the mechanisms of IFN-gamma stimulation by intact staphylococcal microorganisms and by exotoxins differ, and this is likely due to the different receptors which are triggered on the cell membranes. In contrast to its role in the interactions between staphylococci and host cells, IL-18 does not appear to play a major role in superantigen-induced IFN-gamma.

Antigens, Bacterial↗

PubMed2001

Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor-deficient mice.

Dopamine (DA) receptors play an important role in the modulation of excitability and the responsiveness of neurons to activation of excitatory amino acid receptors in the striatum. In the present study, we utilized mice with genetic deletion of D2 or D4 DA receptors and their wild-type (WT) controls to examine if the absence of either receptor subtype affects striatal excitatory synaptic activity. Immunocytochemical analysis verified the absence of D2 or D4 protein expression in the striatum of receptor-deficient mutant animals. Sharp electrode current- and whole cell patch voltage-clamp recordings were obtained from slices of receptor-deficient and WT mice. Basic membrane properties were similar in D2 and D4 receptor-deficient mutants and their respective WT controls. In current-clamp recordings in WT animals, very little low-amplitude spontaneous synaptic activity was observed. The frequency of these spontaneous events was increased slightly in D2 receptor-deficient mice. In addition, large-amplitude depolarizations were observed in a subset of neurons from only the D2 receptor-deficient mutants. Bath application of the K+ channel blocker 4-aminopyridine (100 microM) and bicuculline methiodide (10 microM, to block synaptic activity due to activation of GABA(A) receptors) markedly increased spontaneous synaptic activity in receptor-deficient mutants and WTs. Under these conditions, D2 receptor-deficient mice displayed significantly more excitatory synaptic activity than their WT controls, while there was no difference between D4 receptor-deficient mice and their controls. In voltage-clamp recordings, there was an increase in frequency of spontaneous glutamate receptor-mediated inward currents without a change in mean amplitude in D2 receptor-deficient mutants. In WT mice, activation of D2 family receptors with quinpirole decreased spontaneous excitatory events and conversely sulpiride, a D2 receptor antagonist, increased activity. In D2 receptor-deficient mice, sulpiride had very little net effect. Morphologically, a subpopulation of medium-sized spiny neurons from D2 receptor-deficient mice displayed decreased dendritic spines compared with cells from WT mice. These results provide evidence that D2 receptors play an important role in the regulation of glutamate receptor-mediated activity in the corticostriatal or thalamostriatal pathway. These receptors may function as gatekeepers of glutamate release or of its subsequent effects and thus may protect striatal neurons from excessive excitation.

4-Aminopyridine↗

PubMed2001

Adrenergic and endothelin B receptor-dependent hypertension in dopamine receptor type-2 knockout mice.

Polymorphism of the dopamine receptor type-2 (D(2)) gene is associated with essential hypertension. To assess whether D(2) receptors participate in regulation of blood pressure (BP), we studied mice in which the D(2) receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D(2) homozygous and heterozygous mutant mice than in D(2)+/+ littermates. BP after alpha-adrenergic blockade decreased to a greater extent in D(2)-/- mice than in D(2)+/+ mice. Epinephrine excretion was greater in D(2)-/- mice than in D(2)+/+ mice, and acute adrenalectomy decreased BP to a similar level in D(2)-/- and D(2)+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D(2)-/- mice but not D(2)+/+ mice. ET(B) receptor expression was greater in D(2)-/- mice than in D(2)+/+ mice. In contrast, blockade of ET(A) and V(1) vasopressin receptors had no effect on BP in either D(2)-/- or D(2)+/+ mice. The hypotensive effect of an AT(1) antagonist was also similar in D(2)-/- and D(2)+/+ mice. Basal Na(+),K(+)-ATPase activities in renal cortex and medulla were higher in D(2)+/+ mice than in D(2)-/- mice. Urine flow and sodium excretion were higher in D(2)-/- mice than in D(2)+/+ mice before and after acute saline loading. Thus, complete loss of the D(2) receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D(2) mutant mice may be caused by increased sympathetic and ET(B) receptor activities.

Adrenergic alpha-Antagonists↗

PubMed2001

Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth.

Pulsatile growth hormone (GH) secretion differs between males and females and regulates the sex-specific expression of cytochrome P450s in liver. Sex steroids influence the secretory dynamics of GH, but the neuroendocrine mechanisms have not been conclusively established. Because periventricular hypothalamic somatostatin (SST) expression is greater in males than in females, we generated knockout (Smst(-/-)) mice to investigate whether SST peptides are necessary for sexually differentiated GH secretion and action. Despite marked increases in nadir and median plasma GH levels in both sexes of Smst(-/-) compared with Smst(+/+) mice, the mutant mice had growth curves identical to their sibling controls and retained a normal sexual dimorphism in weight and length. In contrast, the liver of male Smst(-/-) mice was feminized, resulting in an identical profile of GH-regulated hepatic mRNAs between male and female mutants. Male Smst(-/-) mice show higher expression of two SST receptors in the hypothalamus and pituitary than do females. These data indicate that SST is required to masculinize the ultradian GH rhythm by suppressing interpulse GH levels. In the absence of SST, male and female mice exhibit similarly altered plasma GH profiles that eliminate sexually dimorphic liver function but do not affect dimorphic growth.

Animals↗

PubMed2000

Functional uncoupling of adenosine A(2A) receptors and reduced responseto caffeine in mice lacking dopamine D2 receptors.

Dopamine D(2) receptors (Rs) and adenosine A(2A)Rs are coexpressed on striatopallidal neurons, where they mediate opposing actions. In agreement with the idea that D(2)Rs tonically inhibit GABA release from these neurons, stimulation-evoked GABA release was significantly greater from striatal/pallidal slices from D(2)R null mutant (D(2)R(-/-)) than from wild-type (D(2)R(+/+)) mice. Release from heterozygous (D(2)R(+/-)) slices was intermediate. However, contrary to predictions that A(2A)R effects would be enhanced in D(2)R-deficient mice, the A(2A)R agonist CGS 21680 significantly increased GABA release only from D(2)R(+/+) slices. CGS 21680 modulation was observed when D(2)Rs were antagonized by raclopride, suggesting that an acute absence of D(2)Rs cannot explain the results. The lack of CGS 21680 modulation in the D(2)R-deficient mice was also not caused by a compensatory downregulation of A(2A)Rs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D(2)R(+/+) striatal/pallidal slices. This functional uncoupling of A(2A)Rs in the D(2)R-deficient mice was not explained by reduced expression of G(s), G(olf), or type VI adenylyl cyclase. Locomotor activity induced by the adenosine receptor antagonist caffeine was significantly less pronounced in D(2)R(-/-) mice than in D(2)R(+/+) and D(2)R(+/-) mice, further supporting the idea that D(2)Rs are required for caffeine activation. Caffeine increased c-fos only in D(2)R(-/-) globus pallidus. The present results show that a targeted disruption of the D(2)R reduces coupling of A(2A)Rs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D(2)Rs and A(2A)Rs are functionally opposed and that D(2)R-mediated effects normally predominate.

Animals↗

PubMed2000

Selective increase of Nurr1 mRNA expression in mesencephalic dopaminergic neurons of D2 dopamine receptor-deficient mice.

The orphan nuclear receptor Nurr1 is critical for the survival of mesencephalic dopaminergic precursor neurons. Little is known about the mechanisms that regulate Nurr1 expression in vivo. Other members of this receptor family have been shown to be activated by dopamine. We sought to determine if Nurr1 expression is also regulated by endogenous dopamine through dopamine receptors. Consequently, we investigated the expression of Nurr1 mRNA in genetically modified mice lacking both functional copies of the D2 dopamine receptor gene and in their congenic siblings. Quantitative in situ hybridization demonstrated a significant increased expression of Nurr1 mRNA in the substantia nigra pars compacta and the ventral tegmental area of D2 dopamine receptor -/- mice. No change in Nurr1 expression was detected in other brain regions, such as the habenular nuclei and temporal cortex. Among the cell groups studied, mesencephalic dopaminergic neurons are unique in that they express both Nurr1 and the D2 dopamine receptor, and synthesize dopamine. Thus, it seems plausible that the selective increase in Nurr1 expression observed in D2 receptor-deficient mice is the consequence of an impaired dopamine autoreceptor function.

Animals↗

PubMed2000

Adsorption of polyelectrolytes at an oppositely charged surface

We develop a scaling theory of polyelectrolyte adsorption at an oppositely charged surface. At low surface charge densities, the thickness of the adsorbed layer is determined by the balance between electrostatic attraction to the charged surface and chain entropy. At high surface charge densities, it is determined by the balance between electrostatic attraction and short-range monomer-monomer repulsion. These different stabilizing mechanisms result in the nonmonotonic dependence of the layer thickness on the surface charge density.

Journal Article↗

PubMed2000

Unexpected scenario of glass transition in polymer globules: an exactly enumerable model.

We introduce a lattice model of glass transition in polymer globules. This model exhibits ergodicity breaking in which the disjoint regions of phase space do not arise uniformly, but as small chambers whose number increases exponentially with polymer density. Chamber sizes obey power law distribution, making phase space similar to a fractal foam. This clearly demonstrates the importance of the phase space geometry and topology in describing any glass-forming system, such as semicompact polymers during protein folding.

Glass↗

PubMed2000

IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma.

IL-18 shares with IL-1 the same family of receptors and several identical signal transduction pathways. Because of these similarities, IL-18 was investigated for its ability to induce prostaglandin E(2) (PGE(2)) synthesis in human peripheral blood mononuclear cells (PBMC), a prominent, proinflammatory property of IL-1. IL-18 was highly active in PBMC by inducing the synthesis of the chemokine IL-8; however, no induction of PGE(2) synthesis nor cyclooxygenase type-2 gene expression was observed in PBMC stimulated with IL-18. In the same cultures, IL-1beta induced a 12-fold increase in PGE(2). Although IL-1beta-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1beta-induced PGE(2) production by 40%. The suppressive effect of IL-18 on PGE(2) production was mediated by interferon (IFN)-gamma because anti-human IFN-gamma-antibody prevented IL-18-induced reduction in PGE(2). Consistent with these observations, IL-12, a known inducer of IFN-gamma, augmented IL-1beta-induced IFN-gamma but suppressed IL-1beta-induced PGE(2) by 75%. IL-18 binding protein (IL-18BP) is a naturally occurring and specific inhibitor of IL-18. When recombinant IL-18BP was added to PBMC cultures, unexpectedly, spontaneous PGE(2) production increased. PGE(2) production was also increased by the addition of IL-18BP to PBMC stimulated with either IL-1beta or IL-12 and also in whole blood cultures stimulated with Staphylococcus epidermidis. These studies demonstrate that IL-18BP decreases endogenous IL-18 activity by reducing IFN-gamma-mediated responses.

Cells, Cultured↗

PubMed2000

Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18.

A novel, constitutively expressed and secreted IL-18 binding protein (IL-18BP) neutralizes IL-18 and thereby suppresses the production of IFN-gamma, resulting in reduced T-helper type 1 immune responses. In the present study, four human and two mouse isoforms, resulting from mRNA splicing and found in various cDNA libraries, were expressed, purified, and assessed for binding and neutralization of IL-18 biological activities. Human IL-18BP isoform a (IL-18BPa) exhibited the greatest affinity for IL-18 with a rapid on-rate, a slow off-rate, and a dissociation constant (K(d)) of 399 pM. IL-18BPc shares the Ig domain of IL-18BPa except for the 29 C-terminal amino acids; the K(d) of IL-18BPc is 10-fold less (2.94 nM). Nevertheless, IL-18BPa and IL-18BPc neutralize IL-18 >95% at a molar excess of two. IL-18BPb and IL-18BPd isoforms lack a complete Ig domain and lack the ability to bind or neutralize IL-18. Murine IL-18BPc and IL-18BPd isoforms, possessing the identical Ig domain, also neutralize >95% murine IL-18 at a molar excess of two. However, murine IL-18BPd, which shares a common C-terminal motif with human IL-18BPa, also neutralizes human IL-18. Molecular modeling identified a large mixed electrostatic and hydrophobic binding site in the Ig domain of IL-18BP, which could account for its high affinity binding to the ligand. It is likely that preferential secretion of functional and nonfunctional isoforms of IL-18BP affect the immune response.

Amino Acid Sequence↗

PubMed2000

IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1.

Proinflammatory cytokines, including IL-1beta and tumor necrosis factor-alpha (TNF-alpha), promote cancer cell adhesion and liver metastases by up-regulating the expression of vascular cell adhesion molecule-1 (VCAM-1) on hepatic sinusoidal endothelium (HSE). In this study, hepatic metastasis after intrasplenically injected mouse B16 melanoma (B16M) cells was reduced 84-95% in mice with null mutations for either IL-1beta or the IL-1beta-converting enzyme (ICE, caspase-1) compared with wild-type mice. On day 12, 47% of wild-type mice were dead compared with 19% of either IL-1beta or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF-alpha and IL-1beta from cultures of primary murine HSE. The effect of B16M-CM on HSE resulted in increased numbers of B16M cells adhering to HSE, which was completely abrogated by a specific inhibitor of ICE, anti-IL-18 or IL-18-binding protein. Exogenous IL-18 added to HSE also increased the number of adhering melanoma cells; however, this was not affected by IL-1 receptor blockade or TNF neutralization but rather by anti-VCAM-1. These results demonstrate a role for IL-1beta and IL-18 in the development of hepatic metastases of B16M in vivo. In vitro, soluble products from B16M cells stimulate HSE to sequentially release TNF-alpha, IL-1beta, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells.

Animals↗