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Biomedical subjects

R Silverstein

Publications and source records attributed to R Silverstein.

At least 19 recordsLinked to original sources
PubMed1999

Structure-function relationships of bacterial endotoxins. Contribution to microbial sepsis.

A substantial body of knowledge has emerged over the past several decades concerning the primary and tertiary, and quaternary structure of endotoxic LPS and their contribution to the pathogenesis of gram-negative sepsis; however, important questions remain. Among them are the precise three-dimensional configuration of the LPS macromolecule and the contribution of the quaternary structure to the ability of these potent microbial factors to interact with host humoral and cellular inflammatory mediator systems. Also remaining to be sufficiently addressed is the relative contribution of endotoxin interactions with the host to the overall manifestation of disease and conditions under which such contributions serve as the pivotal event in determining outcome. The answers to these questions can be expected to provide valuable insights into potential novel therapeutic intervention strategies and approaches that will ultimately reduce both morbidity and mortality in infection from gram-negative microbes.

Animals↗
PubMed1999

Lipopolyamines: novel antiendotoxin compounds that reduce mortality in experimental sepsis caused by gram-negative bacteria.

The interactions of lipopolyamines, a class of structurally unique compounds currently being used as transfection (lipofection) agents, with lipopolysaccharide (LPS) have been characterized. Our studies have demonstrated that 1,3-di-oleoyloxy-2-(6-carboxyspermyl)-propylamide), available commercially as DOSPER, binds to purified LPS with an affinity of about 1/10 that of polymyxin B. This essentially nontoxic compound inhibits, in a dose-dependent manner, LPS-induced activation of the Limulus clotting cascade and the production of tumor necrosis factor alpha (TNF-alpha) interleukin-6 (IL-6), and nitric oxide from LPS-stimulated J774.A1 cells, a murine macrophage-like cell line. Cytokine inhibition is paralleled by decreased steady-state levels of TNF-alpha and IL-6 mRNA and inhibits the nuclear translocation of nuclear factor kappa B. These findings suggest that the lipopolyamine compound sequesters LPS, thereby blocking downstream cellular activation events that lead to the production of proinflammatory mediators. Administration of DOSPER to D-galactosamine-sensitized mice challenged either with LPS or with Escherichia coli organisms provided significant protection against lethality both with and without antibiotic chemotherapy. Partial protection is evident in LPS-challenged mice treated with DOSPER as late as 2 to 4 h following the endotoxin challenge. A greater degree of protection is observed in E. coli-challenged animals receiving ceftazidime than in those receiving imipenem, which is probably attributable to the higher levels of LPS released in vivo by the former antibiotic. Potent antiendotoxic activity, low toxicity, and ease of synthesis render the lipopolyamines candidate endotoxin-sequestering agents of potential significant therapeutic value.

Animals↗
PubMed1998

Lysosomal integral membrane protein II binds thrombospondin-1. Structure-function homology with the cell adhesion molecule CD36 defines a conserved recognition motif.

LIMPII (lysosomal integral membrane protein II) is one of a family of proteins structurally related to the cell surface glycoprotein CD36. We recently defined a single structural domain on CD36 that mediates binding to adhesive glycoprotein thrombospondin-1 (TSP1). The CD36-TSP1 interaction is known to play a role in platelet-tumor and platelet-monocyte adhesion, angiogenesis, and in monocyte uptake of apoptotic cells. To test whether LIMPII also binds TSP1, a LIMPII peptide corresponding to the TSP1 binding domain of CD36 was expressed as a recombinant glutathione S-transferase (GST) fusion protein. In solid phase binding assays, purified 125I-TSP1 bound to immobilized GST/LIMPII in a time-dependent and saturable manner. Inhibition by excess unlabeled TSP1 or EDTA demonstrated specificity. LIMPII.TSP1 complex formation was specifically blocked by soluble LIMPII fusion protein, by monospecific rabbit IgG directed against the LIMPII peptide and by CD36 fusion proteins containing the TSP1 binding domain. Transfection of Bowes melanoma cells with a chimeric LIMPII cDNA that targets expression to the plasma membrane conferred the ability to bind 125I-TSP1 and to adhere to TSP1-coated surfaces. This study defines a TSP1 binding site conserved between LIMPII and CD36 and suggests that cell surface LIMPII may function in some circumstances as an adhesion receptor for TSP1. Computer-assisted homology searches suggest that the TSP1 recognition motif identified from study of CD36 family members may be widely expressed in nature.

Amino Acid Sequence↗
PubMed1998

CD36 mediates binding of soluble thrombospondin-1 but not cell adhesion and haptotaxis on immobilized thrombospondin-1.

In this study, we examined the binding of soluble TSP1 (and ox-LDL) to CD36-transfected cells and the mechanisms by which immobilized TSP1 mediated attachment and haptotaxis (cell migration towards a substratum-bound ligand) of these transfected cells. CD36 cDNA transfection of NIH 3T3 cells clearly induced a dramatic increase in binding of both soluble [125I]-TSP1 and [125I]-ox-LDL to the surface of CD36-transfected cells, indicating that there was a gain of function with CD36 transfection in NIH 3T3 cells. Despite this gain of function, mock- and CD36-transfected NIH 3T3 cells attached and migrated to a similar extent on immobilized TSP1. An anti-TSP1 oligoclonal antibody inhibited CD36-transfected cell attachment to TSP1 while function blocking anti-CD36 antibodies, alone or in combination with heparin, did not. A series of fusion proteins encompassing cell-recognition domains of TSP1 was then used to delineate mechanisms by which NIH 3T3 cells adhere to TSP1. Although CD36 binds soluble TSP1 through a CSVTCG sequence located within type 1 repeats, 18,19CD36-transfected NIH 3T3 cells did not attach to immobilized type 1 repeats while they did adhere to the N-terminal, type 3 repeats (in an RGD-dependent manner) and the C-terminal domain of TSP1. Conversely, Bowes melanoma cells attached to type 1 repeats and the N- and C-terminal domains of TSP1. However, CD36cDNA transfection of Bowes cells did not increase cell attachment to type 1 repeats compared to that observed with mock-transfected Bowes cells. Moreover, a function blocking anti-CSVTCG peptide antibody did not inhibit the attachment of mock- and CD36-transfected Bowes cells to type 1 repeats. It is suggested that CD36/TSP1 interaction does not occur upon cell-matrix adhesion and haptotaxis because TSP1 undergoes conformational changes that do not allow the exposure of the CD36 binding site.

3T3 Cells↗
PubMed1998

Mechanisms involved in the pathogenesis of sepsis are not necessarily reflected by in vitro cell activation studies.

It is thought that lipopolysaccharide (LPS) from gram-negative bacteria contributes significantly to the pathogenesis of septic shock. In vitro studies to address the mechanisms involved in this process have often investigated human monocytes or mouse macrophages, since these cells produce many of the mediators found in septic patients. Targeting of these mediators, especially tumor necrosis factor alpha (TNF-alpha), has been pursued as a means of reducing mortality in sepsis. Two experimental approaches were designed to test the assumption that in vitro studies with macrophages accurately predict in vivo mechanisms of LPS pathogenesis. In the first approach, advantage was taken of the fact that on consecutive days after injection of thioglycolate into mice, increased numbers of macrophages could be harvested from the peritoneum. These cells manifested markedly enhanced levels of in vitro TNF-alpha, interleukin 6 (IL-6), and nitric oxide production in response to LPS. In D-galactosamine-sensitized mice, however, thioglycolate treatment significantly decreased mortality due to LPS, as well as levels of circulating TNF-alpha and IL-6. Anti-TNF-alpha treatment confirmed this cytokine's role in the observed lethality. In a second experimental approach, we compared the mouse macrophage-stimulating potencies of different LPS preparations with their lethalities to mice. In these studies, the in vitro macrophage-stimulating profiles presented by rough-LPS and smooth-LPS preparations were the reverse of their relative lethal potencies in vivo. In conclusion, peritoneal macrophages appear not to be the major cells responsible for the overall host response during endotoxic shock. These findings underscore the importance of verifying the correlation of in vivo systems with in vitro systems when attributing specific functions to a cell type.

Animals↗
PubMed1997

Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis.

OBJECTIVE: To determine whether the presence of anticardiolipin antibodies (aCL) of a specific IgG subclass is associated with clinical complications of the antiphospholipid antibody syndrome (APS) and whether polymorphisms of Fc receptors for IgG (FcgammaR) with differential binding preferences contribute to an increased risk of thrombotic complications. METHODS: In 60 patients with IgG aCL, we assessed clinical complications of the APS, measured the level of antibody activity, and determined the IgG subclass distribution of aCL by a modified enzyme-linked immunosorbent assay (ELISA) with murine anti-human IgG subclass monoclonal antibodies. Selective IgG subclass adsorption studies were performed to determine the relative contribution of specific IgG subclasses to overall aCL activity. Fcgamma receptor IIA (FcgammaRIIA) genotypes of aCL patients with thrombosis and of non-systemic lupus erythematosus controls were determined by polymerase chain reaction amplification of genomic DNA and allele-specific probes. RESULTS: IgG2 aCL, detected in 75% of the patients, was the major subclass of aCL. Selective adsorption studies demonstrated that IgG2, in contrast to IgG1, was the predominant subclass responsible for aCL reactivity. IgG2 aCL was the only subclass associated with clinical complications, specifically, arterial and/or venous thrombosis (P < 0.04). The presence of FcgammaRIIA-H131, a receptor expressed on platelets, monocytes, and endothelial cells and the only human FcgammaR which efficiently recognizes IgG2, was associated with thrombosis in aCL patients. Among 45 high-titer (>40 GPL [IgG phospholipid] units) aCL patients with thrombosis, 40% were homozygous for FcgammaRIIA-H131, compared with 25% of disease-free controls (P = 0.042). CONCLUSION: While all 4 IgG subclasses are found in autoimmune aCL, only the presence of IgG2 is significantly associated with thrombotic complications. Reactivity in aCL ELISA is largely due to the presence of IgG2 in high-titer patients. The presence of IgG2 aCL, particularly in association with FcgammaRIIA-H131, may be a useful clinical predictor of increased thrombotic risk in patients with autoimmune IgG aCL. Allelic variants of FcgammaRIIA with distinct capacities to interact with IgG subclasses provide a mechanism for genetic susceptibility to an autoantibody-induced prothrombotic state.

Alleles↗
PubMed1996

Combat-related trauma as measured by ego developmental indices of defenses and identity achievement.

The relation between combat-related trauma experience and male ego development and the impact of such trauma on subsequent employment, marital, and legal behavior were investigated empirically. Vietnam combat veterans (N = 52) diagnosed with post-traumatic stress disorder (PTSD) completed the Defense Style Questionnaire (DSQ), the Ego Identity Scale (EIS), and the Impact of Event Scale (IES); 45 noncombat Vietnam-era veterans (not diagnosed with PTSD) completed the DSQ and the EIS. Combat veterans were found to use more maladaptive defenses and have lower levels of identity achievement. Failed marriages, employment problems, and the tendency to experience legal difficulties were more prevalent among the combat veterans. Data analyses showed that identity and defenses do indeed correlate, suggesting that these constitute a unified construct that can be subsumed under the rubric of ego development.

Defense Mechanisms↗
PubMed1995

Bending the conventional rules when treating the ultra-Orthodox in the group setting.

The uniqueness of the ultra-Orthodox Chassidic Jew presents a challenge to the therapist attempting to counsel this population within the group setting. Idiosyncracies of this religious culture highlight the difficulties in prescribing to conventional methodology of group composition and treatment. Proper group composition with an appropriate leader can contribute to the success of group treatment for this population. Suggestions for structuring the group, in consideration of the sensitivities and needs of these members, are presented.

Group Processes↗
PubMed1995

A canine model for determination of the therapeutic index of cytokine inhibitors.

Using tumor necrosis factor (TNF) inhibition in dog blood as a measure of efficacy, and canine emesis as a measure of toxicity, we were able to assign a therapeutic index to rolipram, a prototypic anti-inflammatory compound. Because both assays were performed in the same species, the ambiguities associated with comparing the physiologic effects of drugs on various species was avoided. Rolipram, a standard phosphodiesterase type IV inhibitor, was a prototypic test compound characterized by a number of cardiovascular and central nervous system side effects, as well as its in vitro and in vivo inhibition of TNF. Initial experiments with canine whole blood incubated with lipopolysaccharide resulted in nanogram-per-milliliter concentrations of TNF that could be significantly reduced by in vitro addition of a 0.03 microM concentration of rolipram. Because rolipram inhibited canine TNF production in vitro, a protocol was devised in which TNF inhibitory activity was measured in a series of blood samples from dogs infused with increasingly high doses of rolipram. This yielded the efficacy half of the therapeutic index, whereas the emetogenic dose represented the side effect portion of the index. Rolipram was infused stepwise into conscious dogs at gradually increasing doses. The infusion was stopped when vomiting occurred, and the cumulative dose was reported as the emetic dose. Rolipram caused emesis in dogs at a cumulative dose of 0.1 mg/kg. At each dose of rolipram, blood was collected. The whole blood was incubated in vitro with lipopolysaccharide to induce TNF production, which in turn was quantified by the L929 bio-assay. Theoretically, if the rolipram infusion raised blood values high enough, the rolipram in whole blood would inhibit TNF production and be reflected by a lack of TNF activity in the L929 assay. In this assay system, rolipram's 50% effective dose in the TNF assay was always at least 33-fold lower than its emetic dose of 0.1 mg/kg. This gave rolipram a therapeutic index of at least 33:1 (0.003 versus 0.1 mg/kg) on the basis of its activity in a canine efficacy model (TNF inhibition) and a toxicity model (emesis induction). Experimental compounds were tested for their emetic dose as well as TNF 50% effective dose, with the goal of obtaining a therapeutic index better than that of rolipram. Thus the coupling of cytokine activity with overt toxicity was used to arrive at the therapeutic index of a compound. The therapeutic index was used to rank compounds as to their efficacy/toxicity profile. This ranking was used to eliminate several anti-inflammatory compounds that had a therapeutic index less than that of rolipram.

Animals↗
PubMed1994

MRI assessment of the normal temporomandibular joint with the use of projective geometry.

A new analysis, the Projective Invariant Analysis, was developed for the evaluation of magnetic resonance images of the temporomandibular joint. This method was used because it takes into account factors such as linear and angular measurements that simple Euclidean geometric methods fail to address. Forty "normal" joints (20 subjects) and 65 "abnormal" joints were analyzed. Joints were defined as normal if they had a Class I skeletal pattern and a Class I occlusion. In addition, a history was obtained and a clinical examination was performed on each of these subjects to rule out any temporomandibular joint dysfunction, masticatory muscle myalgia, or cervicalgia. The images of the 40 normal joints were compared with 65 previously taken images of 53 patients with conditions that had been diagnosed as anteriorly displaced disks with reduction. These two groups were compared with the use of the analysis method described by Drace and Enzmann that uses angular measurements. The groups were also analyzed with the use of a new method in which the structural relationships of the articular eminence, gleniod fossa, mandibular condyle, and articular disk were related to each other using projective geometry. For the projective invariant analysis, a 95% confidence ellipse was constructed on the basis of the normal data. All but one of the 40 normal points fell within this ellipse, and only three of the 65 abnormal points were inside the ellipse. Both analyses showed a significant difference between the normal and abnormal groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Contribution of tumor necrosis factor-alpha and glucocorticoid in hydrazine sulfate-mediated protection against endotoxin lethality.

Hydrazine sulfate pretreatment has previously been shown in our laboratory to protect normal mice against endotoxin and D-galactosamine-sensitized mice against both exogenous tumor necrosis factor (TNF) and endotoxin. An intact pituitary is required for manifestation of the protective effects. Further, we have demonstrated that hydrazine sulfate pretreatment specifically modulates the TNF response to lipopolysaccharide (LPS) in mouse macrophages in vitro. This in vivo study was performed to test whether a reduced TNF response and/or increased glucocorticoid response may contribute to hydrazine sulfate protection against LPS-induced lethality in vivo. The results presented here establish that hydrazine sulfate pretreatment selectively attenuates circulating TNF levels following LPS challenge. Moreover, adrenalectomy abrogates hydrazine sulfate protection but does not prevent hydrazine sulfate attenuation of circulating TNF levels in response to LPS. Hydrazine sulfate-mediated protection is, however, restored permissively by corticosterone. Thus, the mechanism by which hydrazine sulfate protects against LPS lethality in adrenalectomized mice includes TNF modulation in response to endotoxin, as well as a pivotal requirement for glucocorticoid.

Adrenalectomy↗
PubMed1993

Hypercoagulable states.

PURPOSE: To describe the major pathophysiologic mechanisms underlying inherited and secondary hypercoagulable states and to evaluate the frequency, natural history, diagnosis, and management of the various clinical disorders. DATA SOURCES AND STUDY SELECTION: Relevant clinical literature obtained from bibliographies in hematology textbooks and from computerized indexes was reviewed. A hypothesis was formed based on this literature review and on recent developments from a number of experimental studies. DATA SYNTHESIS: Hypercoagulable states include various inherited as well as acquired clinical disorders characterized by an increased risk for thromboembolism. Primary hypercoagulable states include relatively rare inherited conditions that lead to disordered endothelial cell thromboregulation. These conditions include decreased thrombomodulin-dependent activation of activated protein C, impaired heparin binding of antithrombin III, or down-regulation of membrane-associated plasmin generation. The major, inherited, inhibitor disease states include antithrombin III deficiency, protein C deficiency, and protein S deficiency and should be considered in patients who have recurrent, familial, or juvenile deep-vein thrombosis or occlusion in an unusual location such as a mesenteric, brachial, or cerebral vessel. Secondary hypercoagulable states may be seen in many heterogeneous disorders. In many of these conditions, endothelial activation by cytokines leads to loss of normal vessel-wall anticoagulant surface functions with conversion to a proinflammatory thrombogenic phenotype. Important clinical syndromes associated with substantial thromboembolic events include the antiphospholipid syndrome, heparin-induced thrombopathy, the myeloproliferative syndromes, and cancer. CONCLUSIONS: Physiologic thromboregulation occurs at the vessel-wall surface. Quantitative and qualitative deficiencies of normal, steady-state endothelial anticoagulant activities are associated with primary hypercoagulable states. Activated endothelial cell surfaces express a thrombogenic phenotype and contribute to secondary or acquired hypercoagulability.

Blood Coagulation Disorders↗
PubMed1993

Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-alpha production and protect mice against endotoxin challenge.

Adenosine (ADO) and its structurally related analogues are known to regulate the activities of immune and inflammatory cells, including a number of key functions of mononuclear phagocytes. In this study ADO and the synthetic ADO analogue MDL201112 inhibited TNF-alpha, but not IL-1, production by activated mouse peritoneal macrophages and the macrophage-like cell lines J774 and RAW-264. Northern blot analysis indicated that MDL201112 selectively inhibited the expression of steady-state TNF-alpha RNA in LPS+IFN-gamma-activated J774 and RAW-264 cells. This effect could not be attributed to changes in TNF-alpha RNA stability. In contrast, ADO had no effect on RNA levels for TNF-alpha and IL-1, suggesting that ADO acts at a post-transcriptional biosynthetic step. To determine whether either compound inhibited TNF-alpha-mediated inflammatory responses, mice were treated with ADO or MDL201112 and challenged with a lethal dose of endotoxic LPS and D-galactosamine, an hepatotoxin that sensitizes mice to lethal LPS challenge. A single i.p. injection of MDL201112 (100 mg/kg) protected over 90% of the mice, whether injected 1 h before or at the time of LPS challenge. MDL201112 also inhibited the appearance of TNF-alpha in the serum of LPS-challenged animals. The compound did not block D-galactosamine sensitization nor did it prevent lethality caused by the injection of rTNF-alpha. ADO failed to protect animals against endotoxin lethality, most likely due to the rapid metabolism of the nucleoside in vivo. These results establish ADO and MDL201112 as potent inhibitors of TNF-alpha biosynthesis and suggest that MDL201112 or similar analogues warrant further study as potential agents for the treatment of endotoxin shock and other diseases in which TNF-alpha plays an important pathogenic role.

Adenine↗
PubMed1993

Activated platelets form protected zones of adhesion on fibrinogen and fibronectin-coated surfaces.

Leukocytes form zones of close apposition when they adhere to ligand-coated surfaces. Because plasma proteins are excluded from these contact zones, we have termed them protected zones of adhesion. To determine whether platelets form similar protected zones of adhesion, gel-filtered platelets stimulated with thrombin or ADP were allowed to adhere to fibrinogen- or fibronectin-coated surfaces. The protein-coated surfaces with platelets attached were stained with either fluorochrome-conjugated goat anti-human fibrinogen or anti-human fibronectin antibodies, or with rhodamine-conjugated polyethylene glycol polymers. Fluorescence microscopy revealed that F(ab')2 anti-fibrinogen (100 kD) did not penetrate into the contact zones between stimulated platelets and the underlying fibrinogen-coated surface, while Fab antifibrinogen (50 kD) and 10 kD polyethylene glycol readily penetrated and stained the substrate beneath the platelets. Thrombin- or ADP-stimulated platelets also formed protected zones of adhesion on fibronectin-coated surfaces. F(ab')2 anti-fibronectin and 10 kD polyethylene glycol were excluded from these adhesion zones, indicating that they are much less permeable than those formed by platelets on fibrinogen-coated surfaces. The permeability properties of protected zones of adhesion formed by stimulated platelets on surfaces coated with both fibrinogen and fibronectin were similar to the zones of adhesion formed on fibronectin alone. mAb 7E3, directed against the alpha IIb beta 3 integrin blocked the formation of protected adhesion zones between thrombin-stimulated platelets and fibrinogen or fibronectin coated surfaces. mAb C13 is directed against the alpha 5 beta 1 integrin on platelets. Stimulated platelets treated with this mAb formed protected zones of adhesion on surfaces coated with fibronectin. These protected zones were impermeable to F(ab')2 antifibronectin but were permeable to 10 kD polyethylene glycol. These results show that activated platelets form protected zones of adhesion and that the size of molecules excluded from these zones depends upon the composition of the matrix proteins to which the platelets adhere. They also show that formation of protected zones of adhesion by platelets requires alpha IIb beta 3 integrins while the permeability properties of these zones of adhesion are regulated by both alpha IIb beta 3 and alpha 5 beta 1 integrins.

Blood Platelets↗
PubMed1993

Endogenous and exogenous glucocorticoids have different roles in modulating endotoxin lethality in D-galactosamine-sensitized mice.

Endotoxin sensitivity and dexamethasone protection have been assessed in mice that were adrenalectomized and also treated with D-galactosamine at the time of endotoxin challenge. Our data establish that adrenalectomy did not detectably alter the magnitude of the increased sensitivity induced by D-galactosamine alone. Furthermore, protection provided by acute exogenous glucocorticoid treatment was still demonstrable in these mice and was not influenced by chronic experimentally induced glucocorticoid deficiency. Our data confirm that the adrenalectomized mouse model of endotoxin lethality is characterized by increased sensitivity to endotoxin and establish that the magnitude of this sensitizing effect is more than 100-fold. We also show for the first time that adrenalectomy causes an appreciable kinetic shift in the endotoxic crisis and that dexamethasone, given at the time of endotoxin challenge, will significantly reverse the increased sensitivity to lethality. Our results indicate that the protective effects of corticosteroids may involve important chronic as well as acute responses. In particular, we conclude that endogenous glucocorticoid need not always increase host resistance to endotoxin, nor does such a circumstance eliminate the possibility for exogenous glucocorticoid-mediated protective effects.

Adrenalectomy↗
PubMed1993

An interleukin-6-induced acute-phase response does not confer protection against lipopolysaccharide lethality.

Lipopolysaccharide (LPS), a component of gram-negative bacterial outer cell walls, can stimulate lymphoreticular cells to produce cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. One of these proinflammatory cytokines, IL-6, induces hepatic synthesis of a class of proteins termed acute-phase proteins. D-Galactosamine inhibits acute-phase protein synthesis and concurrently sensitizes mice to a lethal dose of LPS approximately 10,000-fold. From these observations, we hypothesized that the acute-phase response may serve as a defense mechanism for protection of the host against the deleterious effects of LPS. To test this hypothesis, murine recombinant IL-6 (mrIL-6) was used to induce an acute-phase response prior to a lethal LPS challenge in both D-galactosamine-treated and normal mice. Induction of the acute-phase response by mrIL-6 was quantitated by measuring the concentrations of fibrinogen and complement component C3, two well-characterized acute-phase proteins, in the circulation. The effect of acute-phase and normal serum on TNF-alpha release by peritoneal macrophages stimulated with LPS in vitro was also examined. The results of these studies confirmed the induction of the acute-phase response by mrIL-6, as reflected in an approximate doubling in circulating levels of fibrinogen and C3. However, when either D-galactosamine-sensitized or normal mice were challenged with a lethal dose of LPS at various times after mrIL-6 administration, the acute-phase response induced by mrIL-6 did not alter either cumulative lethality or the kinetics of lethality. Additionally, compared with normal serum, acute-phase serum did not affect TNF-alpha release by peritoneal macrophages following LPS-mediated stimulation in vitro. Collectively, these studies would not support a dominant role for an IL-6-mediated acute-phase response as contributing to the resistance of normal mice compared with D-galactosamine-sensitized mice in LPS-induced lethal toxicity.

Acute-Phase Reaction↗