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Biomedical subjects

P Libby

Publications and source records attributed to P Libby.

At least 199 records · Page 11Linked to original sources
PubMed1993

Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma.

Vascular cell adhesion molecule-1 (VCAM-1), a mononuclear leukocyte adhesion molecule, is expressed in cultured vascular endothelial cells activated by cytokines and is induced in rabbit aortic endothelium in vivo within 1 week after initiation of an atherogenic diet. We now demonstrate that vascular smooth muscle cells can also express VCAM-1 in rabbit atherosclerotic lesions in vivo and in response to cytokines in vitro. Immunohistochemical staining of aortas from rabbits fed a 0.3% cholesterol-containing diet revealed that a portion of smooth muscle cells within intimal foam cell-rich lesions expressed VCAM-1. The intimal VCAM-1-expressing cells localized predominantly in regions above the internal elastic lamina. These VCAM-1-positive cells had the typical spindle shape of smooth muscle cells but had reduced alpha-actin expression in comparison to normal medial smooth muscle cells, and did not bear markers for endothelium, macrophages, and T cells. In culture, rabbit aortic smooth muscle cells expressed VCAM-1 mRNA and protein in a time- and concentration-dependent fashion when exposed to interferon-gamma or Gram-negative bacterial lipopolysaccharide. Cultured human vascular smooth muscle cells also expressed VCAM-1 mRNA and protein in response to lipopolysaccharide, interferon-gamma, and interleukin-4. The monokines interleukin-1 alpha and tumor necrosis factor-alpha did not induce VCAM-1 expression in either rabbit or human vascular smooth muscle cells. Inducible VCAM-1 expression by vascular smooth muscle cells in vivo during hypercholesterolemia and in vitro in response to certain cytokines suggests a broader range of VCAM-1 functions in vascular biology than heretofore appreciated.

Actins↗
PubMed1993

Cryopreserved aortic homografts contain viable smooth muscle cells capable of expressing transplantation antigens.

Frozen aortic tissue is increasingly used as homografts in reconstructive cardiovascular surgical procedures. The viability of cells within these cryopreserved tissues, their identity, and their potential immunogenicity have been the subject of controversy. We cultured cells from cryopreserved human aortic homografts that reacted with a monoclonal antibody that recognizes muscle actin isoforms, identifying them as smooth muscle cells. Under basal conditions, these smooth muscle cells contained messenger ribonucleic acid for class I human leukocyte antigens detected by northern blotting and expressed class I human leukocyte antigen on their surfaces as measured by enzyme-linked immunoassay and immunohistochemistry. Unstimulated smooth muscle cells contained no class II human leukocyte antigen messenger ribonucleic acid as determined by northern blotting and displayed almost no class II surface antigen as determined by enzyme-linked immunoassay. Interferon gamma (1000 U/ml, 72 hours), a product of activated T lymphocytes, not only increased the expression of class I human leukocyte antigens by smooth muscle cells, but induced class II human leukocyte antigen messenger ribonucleic acid and elevated surface expression from 22 +/- 7 to 819 +/- 35 enzyme-linked immunoassay units (n = 4). Immunohistochemistry revealed few class II-positive smooth muscle cells under basal culture conditions, but all cells showed high levels of DR antigen after exposure to interferon gamma for 3 days. Similar results were obtained in two independent isolates. We conclude that cryopreserved aortic homografts can contain viable smooth muscle cells capable of expressing major histocompatibility antigens that might render them immunogenic and susceptible to rejection by the recipient's immune system.

Aorta↗
PubMed1992

Do vascular wall cytokines promote atherogenesis?

Protein mediators commonly associated with inflammatory and immune responses may also convey signals among vascular endothelial and smooth muscle cells, thereby mediating the evolution of hyperplastic arterial disease. A picture is emerging in which cytokine expression, lipoprotein modification, and atheroma development are interlocking processes.

Arteriosclerosis↗
PubMed1992

Increased apolipoprotein E and c-fms gene expression without elevated interleukin 1 or 6 mRNA levels indicates selective activation of macrophage functions in advanced human atheroma.

Cells found within atherosclerotic lesions can produce in culture protein mediators that may participate in atherogenesis. To test whether human atheromata actually contain transcripts for certain of these genes, we compared levels of mRNAs in carotid or coronary atheromata and in nonatherosclerotic human vessels by polymerase chain reaction (PCR) amplification of cDNAs reverse-transcribed from RNA. We measured PCR products (generated during exponential amplification) by incorporation of 32P-labeled primers. Levels of interleukin 1 alpha, 1 beta, or 6 mRNAs in plaques and controls did not differ. Compared to uninvolved vessels, plaques did contain higher levels of mRNA encoding platelet-derived growth factor A chain (42 +/- 24 vs. 12 +/- 10 fmol of product; mean +/- SD; n = 8 and 8, respectively; P = 0.007) and B chain (41 +/- 36 vs. 4 +/- 3 fmol of product, n = 14 and 6, respectively; P = 0.024). Atherosclerotic lesions consistently had much higher levels of apolipoprotein E (apoE) mRNA than did control vessels (131 +/- 71 vs. 5 +/- 3 fmol of product; n = 12 and 10, respectively; P less than 0.001). Direct RNA blot analyses confirmed elevated levels of apoE mRNA in plaque extracts. To test whether mononuclear phagocytes might be a source of the apoE mRNA, we studied a selective marker for cells of the monocytic lineage, the c-fms protooncogene, which encodes the receptor for macrophage colony-stimulating factor. Plaques also contained elevated levels of c-fms mRNA (30 +/- 17 vs. 5 +/- 3 fmol of product; n = 10 and 7, respectively; P = 0.002). Immunohistochemical colocalization demonstrated apoE protein in association with macrophages in plaques, whereas nonatherosclerotic vessels showed no immunoreactive apoE. ApoE produced locally in atheroma might modulate the functions of lesional T cells or promote "reverse cholesterol transport" by associating with high density lipoprotein particles, thus targeting them for peripheral uptake. Macrophages within the advanced human atheroma appear to exhibit a selective program of activation as they express high levels of apoE, whereas overall levels of interleukin 1 or 6 mRNAs in plaques are not elevated.

Apolipoproteins E↗
PubMed1992

Functional significance of human vascular smooth muscle cell-derived interleukin 1 in paracrine and autocrine regulation pathways.

Interleukin 1 (IL1), a key mediator in the cytokine network, alters many pathophysiologically important functions of blood vessel wall cells. Vascular cells, such as endothelial cells and smooth muscle cells (SMC) can themselves transcribe IL1 genes, raising the possibility that IL1 regulates blood vessel wall functions by local autocrine or paracrine mechanisms. However, IL1 lacks a recognizable signal sequence and it is still unclear how vascular cells might release IL1 or if IL1 derived from vascular cells can actually produce autocrine or paracrine effects. We explored these issues in human vascular SMC, the most numerous cell type in arteries and veins, using cultured SMC and short term organoid cultures. SMC treated with lipopolysaccharide recombinant tumor necrosis factor (recTNF), or recIL1 itself ("activated SMC") elaborated thymocyte costimulatory activity, a biological activity traditionally ascribed to IL1. However, neutralization experiments with monospecific antibodies disclosed that the more recently recognized cytokine IL6 rather than IL1 accounted for most of the soluble thymocyte costimulatory activity released by activated SMC. Using the D10S assay that distinguishes IL1 from IL6 and TNF we found that the culture supernatant of activated SMC contained little or no IL1, but that the cytosol and surface of these cells did exhibit this activity. Antiserum to recIL1 alpha inhibited stimulation of D10S cells by surface-associated IL1 of activated SMC, while treatment with acid to elute receptor- or nonspecifically bound IL1 did not abrogate this D10S proliferation. Short term organoid cultures of both normal veins and human arteriosclerotic plaque also expressed tissue-associated IL1 activity upon stimulation with LPS but did not release significant soluble IL1 activity. To establish further the biological functions of cell-associated IL1, we incubated stimulated or unstimulated SMC that were fixed with paraformaldehyde and washed extensively (fixed SMC) with overlayered viable SMC of the same donor (responder SMC). Contact with fixed SMC that bore surface IL1 following TNF or IL1 stimulation evoked up to 20-fold higher IL6 release from responder SMC than did exposure to unstimulated SMC (57 vs 1052 ng/ml/day). Addition of anti-IL1 antibody inhibited the release of IL6 from the responder SMC. These results demonstrate that cytokine-activated SMC express biologically active IL1 on their cell surface and illustrate how these cells might actually participate in autocrine and paracrine signaling in the vessel wall. The requirement for direct intercellular contact for IL1 effects could facilitate local information exchange among vascular wall cells and/or infiltrating leukocytes and permit costimulation while limiting undue propagation of inflammatory stimuli.

Animals↗
PubMed1992

Atherogenic diets enhance endotoxin-stimulated interleukin-1 and tumor necrosis factor gene expression in rabbit aortae.

Cytokine-induced vascular changes may contribute to the atherogenic process. We examined the effect of atherogenic diets on the aortic expression of genes for the cytokines interleukin-1 alpha and beta and tumor necrosis factor alpha. Male New Zealand White rabbits were fed one of the following diets for 10 wk: nonpurified diet, a semipurified diet with 10% corn oil, a semipurified diet with 1% corn oil and 9% partially hydrogenated coconut oil, or the 9% coconut oil diet supplemented with either 0.1, 0.3 or 0.9% added cholesterol (n = 6/group). At 10 wk, 3 rabbits per group received lipopolysaccharide (200 micrograms/kg) intravenously. After 1.5 h the rabbits were killed and their aortae removed and analyzed. Histologic examination showed that the 0.3% and 0.9% cholesterol-fed rabbits developed appreciable aortic lesions. Diet had no major effect on the basal levels of aortic cytokine mRNA as determined by polymerase chain reaction analysis of DNAs. However, aortic tissue from rabbits fed 0.3% and 0.9% cholesterol diets showed significantly enhanced lipopolysaccharide-evoked levels of mRNA encoding interleukin-1 alpha (392 +/- 91 for saturated fat vs. 759 +/- 191 and 800 +/- 120 fmoles/reaction for 0.3% and 0.9% cholesterol), interleukin-1 beta (99 +/- 10 vs. 353 +/- 80 and 355 +/- 86) and tumor necrosis factor alpha (195 +/- 15 vs. 594 +/- 78 and 667 +/- 97). Extracts of aortae from rabbits injected with lipopolysaccharide contained interleukin-1 and tumor necrosis factor alpha activity but differences in biological activity due to diet were not detectable at the 1.5 h time point (chosen for maximal mRNA expression). Increased local cytokine gene expression in response to acute stimulus might influence the evolution of the vascular response to diets rich in cholesterol and saturated fats.

Animals↗
PubMed1992

Cytokines as mediators of vascular pathology.

Interactions between leukocytes and intrinsic vascular wall cells characterize many inflammatory reactions and contribute importantly to the pathogenesis of many vascular diseases. In view of this intimate involvement of leukocytes in vascular pathology it is important to understand the signals that recruit and activate leukocytes locally in regions of vascular pathology. It is also desirable to delineate the mechanisms by which leukocytes influence the behavior of intrinsic vascular wall cells in ways which may contribute to vascular lesion formation. Mediators elaborated by leukocytes include small molecules including lipid-derived mediators such as prostanoids, leukotrienes, and platelet activating factor. Leukocytes can also produce protein mediators including those currently classified as cytokines. The cytokines, protein mediators involved in inflammation and control of the immune response, derive from all classes of leukocytes studied. Local cytokine networks may orchestrate complex programs of expression of functions of leukocytes and endothelial and smooth muscle cells involved in vascular homeostasis and pathology. Our laboratory has been interested in hyperplastic arterial diseases including atherosclerosis and restenosis following angioplasty treatment of obstructive atherosclerosis. Definitive evidence for roles of cytokines in the pathogenesis of these syndromes are lacking. However, various in vitro and in vivo studies have furnished sufficient information to permit formulation of rather detailed hypotheses or models. In hypercholesterolemic rabbits vascular cell adhesion molecule-l (VCAM-l) may participate in initial monocyte recruitment to prelesional areas of arterial endothelium. Other adhesion molecules including Intercellular adhesion molecule-l (ICAM-l) may also participate in monocyte adhesion to arterial endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1992

Cytokines and growth factors in atherogenesis.

The development of laboratory techniques for the culturing of vascular endothelial and smooth-muscle cells during the 1970s, followed by the rapid advances in molecular and cell biology during the 1980s, provided the foundation for the identification of growth factor and cytokine networks involved in maintenance of the normal vasculature as well as participating in diverse pathologic processes involving blood vessels. Vascular cells can produce and respond to a vast array of biochemical messengers that control cell replication, differentiation, and many specific cell functions. Investigators are beginning to explore the changes in the patterns of messengers exchanged between the vascular cells and infiltrating leukocytes during the initiation and progression of atherosclerosis. A variety of in vitro and in vivo studies have indicated that growth factors and cytokines that mediate the critical processes of inflammation and wound healing also play a central role in vascular disease. Indeed, many view atherosclerosis as the result of excessive or prolonged chronic inflammation and wound healing in response to diverse injurious stimuli to cells of the vessel wall. Vascular injury may result from many varied and interacting forces, including nutritional and metabolic abnormalities such as hyperlipidemias or elevated homocysteine, mechanical forces associated with hypertension, exogenous toxins including those found in cigarette smoke, abnormally glycated proteins associated with diabetes mellitus, oxidatively modified lipids or proteins, and, possibly, viral infections. Ultimately, a greater understanding of the activated cytokine and growth factor networks within the vascular wall following injury and during atherogenesis will allow clinical scientists to identify steps susceptible to therapeutic intervention using recombinant cytokines, antibodies, soluble receptors, or receptor antagonists. Other therapeutic strategies may involve the transfection of specific genes, which may inhibit atherosclerosis, into vascular cells at sites prone to lesion formation.

Animals↗
PubMed1992

Interferon-beta. A potential autocrine regulator of human vascular smooth muscle cell growth.

Positive and negative signals regulate the proliferation in vitro of vascular smooth muscle cells (SMC), a principle cell type in the blood vessel wall. Immune interferon (IFN-gamma, a type II IFN) retards the growth of human SMC, but the effect of type I IFN (IFN-alpha or beta) is unknown. Furthermore, the capacity of SMC to produce IFN is uncharacterized. If type I IFN alters SMC growth and is produced by this cell type, an autocrine inhibitory loop could operate in vascular growth control. To test this possibility, we compared the effects of IFN-alpha, beta, and gamma on the growth of SMC stimulated by platelet-derived growth factor, interleukin-1 or tumor necrosis factor alpha. IFN-beta and IFN-gamma, but not IFN-alpha, consistently retarded growth of SMC cultures (measured by net DNA accumulation and cell number). We investigated whether SMC could produce IFN-beta, a mediator characteristically produced by fibroblasts. Vascular SMC treated with poly(I):poly(C) or tumor necrosis factor-alpha expressed IFN-beta mRNA. SMC treated with poly(I):poly(C) or Newcastle Disease virus elaborated biologically active IFN-beta as well. Our results establish that IFN-beta inhibits human vascular SMC growth and that these cells can express the IFN-beta gene. These findings show that human vascular SMC have the capacity of producing a potential autocrine growth regulator.

Base Sequence↗
PubMed1992

Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis.

The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterizes early atherogenesis. Macrophages are also present in more advanced human atherosclerotic plaques and can produce many mediators that may contribute to lesion formation and progression. Macrophage colony-stimulating factor (MCSF) enhances the proliferation and differentiation of monocyte progenitors and is required for the survival and activation of mature monocytes and macrophages. The authors therefore examined the expression of the MCSF gene in cultured human vascular endothelial (EC) and smooth muscle cells (SMC) as well as in atheromatous lesions from rabbits and humans. Growth arrested EC and SMC contain a low level of MCSF mRNA. Bacterial lipopolysaccharide (LPS), recombinant human interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor alpha (TNF alpha) induced MCSF mRNA accumulation in a concentration-dependent manner in both EC and SMC. These stimuli induced large increases in MCSF mRNA with peak induction between 4-8 hours after treatment. LPS, IL-1 alpha, and TNF alpha stimulated EC and SMC also showed increased fluorescent antibody staining for MCSF protein and released immunoreactive MCSF in a time-dependent manner. In contrast, phorbol 12-myristate 13-acetate (PMA) was a less potent inducer of MCSF gene expression and iron-oxidized low-density lipoproteins (ox-LDL) did not increase consistently MCSF mRNA or the synthesis and secretion of immunoreactive protein. Northern analysis of mRNA isolated from the atheromatous aorta of rabbits fed a 1% cholesterol diet for 10 weeks showed elevated MCSF mRNA compared with controls. Immunostaining of atheromatous arterial lesions of rabbits demonstrated MCSF protein in association with intimal SMC as well as macrophages. Furthermore, polymerase chain reaction (PCR) analysis of MCSF mRNA in human atheromata showed higher levels than found in nonatherosclerotic arteries and veins. Since the authors found no mRNA for the MCSF receptor, c-fms, in cultured EC or SMC macrophages are likely the primary target for MCSF within atheromatous vessels. The authors therefore investigated the effects of MCSF on monocyte functions related to foam cell development. Treatment of cultured human monocytes with recombinant human MCSF (10(3) U/ml, 72 hr) led to the accumulation of mRNA for the acetyl-LDL (scavenger) receptor and apolipoprotein E (apo E). These studies establish that vascular EC and SMC produce substantial MCSF in response to a variety of stimuli. The local production of MCSF during atherogenesis may contribute to macrophage survival and proliferation or activate specific macrophage functions such as expression of the scavenger receptor and secretion of apo E.

Animals↗
PubMed1991

Interleukin-1 gene expression in rabbit vascular tissue in vivo.

Cultured human vascular endothelial and smooth muscle cells express interleukin-1 (IL-1) genes when exposed to bacterial lipopolysaccharides (LPS) and a variety of inflammatory mediators. Local production of IL-1 may contribute to the pathogenesis of various vascular diseases. Therefore the ability of intact vascular tissue to accumulate IL-1 mRNA and synthesize de novo biologically active IL-1 protein was examined. Escherichia coli LPS (10 micrograms/kg) was administered intravenously to adult rabbits and total RNA was isolated from aortic tissue at various times after LPS injection. In saline-injected rabbits, RNA extracted from the thoracic aorta contained little or no IL-1 message detected by Northern analysis using IL-1 alpha and beta cDNA probes cloned from an LPS-stimulated rabbit splenic macrophage library. Lipopolysaccharide treatment promptly induced transient accumulation of mRNA for IL-1 alpha and IL-1 beta within the aorta (maximal 1-hour after injection). Short-term organoid cultures of rabbit aorta exposed to LPS in vitro synthesized immunoprecipitable IL-1 alpha protein. Extracts of aortic tissue excised 1.5 to 3.0 hours after intravenous LPS administration contained immunoreactive and biologically active IL-1 alpha. Anti-rabbit IL-1 alpha antibody neutralized the biologic activity (more than 90%). Microscopic and immunohistochemical studies did not disclose adherent or infiltrating macrophages in rabbit aorta at the time of maximal IL-1 mRNA accumulation after LPS administration (1.5 hours), indicating that intrinsic vascular wall cells rather than mononuclear phagocytes probably account for the IL-1 activity induced by LPS. In addition, aortic tissue from rabbits fed an atherogenic diet showed an enhanced ability to accumulate IL-1 alpha and beta mRNA and produce immunodetectable protein in response to LPS administration. These studies demonstrate inducible IL-1 gene expression in rabbit vascular tissue in vivo and support a local role for this cytokine in vascular pathophysiology.

Animals↗
PubMed1991

Human coronary transplantation-associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial cells.

Occlusive disease of coronary arteries of engrafted hearts is the major obstacle to long-term survival of human cardiac allografts. The pathogenesis of this process remains uncertain. The identity and localization of cells found in transplantation-associated arteriosclerosis lesions from human cardiac allografts were evaluated, and their expression of class II major histocompatibility complex (human leukocyte antigen-DR [HLA-DR]), surface molecules required for recognition of foreign cells by CD4+ T lymphocytes, was noted. Expanded intimas of transplanted coronary arteries contain T lymphocytes (both CD4+ and CD8+ in approximately equal number) and HLA-DR+ macrophages, both localized primarily in a ring immediately below the luminal endothelium, a distribution strikingly different from that in typical atherosclerosis. Coronary arterial endothelium from six of six transplanted hearts studied bore high levels of HLA-DR. Normal human arteries or usual atherosclerotic lesions have few if any HLA-DR+ endothelial cells. The significance of these findings was tested by evaluating the ability of HLA-DR+ arterial cells to interact with allogeneic T cells in vitro. Endothelial cells (but not smooth muscle cells) cultured from human arteries stimulated foreign CD4+ T cells to proliferate and augmented their secretion of interleukin-2. These findings suggest that ongoing stimulation of recipient T lymphocytes by HLA-DR+ endothelium of donor coronary arteries contributes to a sustained regional immune response. Consequent local release of cytokines may regulate smooth muscle cell proliferation and matrix accumulation within the coronary arteries of allografted hearts.

CD4 Antigens↗
PubMed1990

Cytokine induction by lipopolysaccharide (LPS) corresponds to lethal toxicity and is inhibited by nontoxic Rhodobacter capsulatus LPS.

Many pathological effects of gram-negative bacteria are produced by their cell wall-derived lipopolysaccharides (LPSs). Differing pathogenicity of gram-negative LPSs, however, may depend on their capacities to induce cytokines. Thus, we studied the lethal toxicity of four nonenterobacterial LPSs and compared it with their capacity to induce mononuclear cell (MNC)-derived interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Unstimulated MNC did not release these cytokines. LPS from the phototrophic strain Rhodobacter capsulatus 37b4 elaborated little toxicity in galactosamine-treated mice (10 micrograms of LPS per mouse was the 100% lethal dose [LD100]) and induced IL-1 and IL-6 release only at high concentrations (10 to 50 micrograms of LPS per ml). R. capsulatus LPS failed to induce TNF activity even at the highest concentration tested (100 micrograms of LPS per ml). In contrast, LPS derived from Pseudomonas diminuta NCTC 8545 or the nodulating species Bradyrhizobium lupini DSM 30140 and Rhizobium meliloti 10406 expressed lethal toxicity (LD100, 1,000, 100, and 10 ng per mouse, respectively) and induced IL-1 or IL-6 (10 to 100, 10, and 1 ng of LPS per ml, respectively) at concentrations 1,000- to 10,000-fold lower than effective levels of R. capsulatus LPS. LPSs from P. diminuta, B. lupini, and R. meliloti also stimulated TNF production and release. MNC accumulated cell-associated IL-1 activities under circumstances in which released activity was readily detected. The cells contained only scant IL-6 activity, indicating release of this mediator rather than intracellular accumulation. Antisera to the respective cytokines inactivated biological activities of the samples selectively. The R. capsulatus LPS inhibited cytokine induction by LPS from P. diminuta, B. lupini, and R. meliloti in coincubation experiments. These results show that the in vivo lethality of the LPSs tested correlates with the induction of monocyte-derived cytokines in vitro. The results of this study suggest that the different lethality of various LPSs from gram-negative bacteria may be due to the differential ability of these LPSs to induce cytokine production.

Animals↗