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Biomedical subjects

J D Sipe

Publications and source records attributed to J D Sipe.

At least 73 records · Page 4Linked to original sources
PubMed1989

Serum amyloid A gene expression and AA amyloid formation in A/J and SJL/J mice.

Serum amyloid A (SAA) gene expression and AA amyloid fibril formation were studied in A/J and SJL/J mice, two strains which have been reported to possess defects in AA fibril formation. Four types of inflammatory stimulation were employed: acute inflammation stimulated with lipopolysaccharide (LPS), chronic inflammation with casein in complete Freund's adjuvant, amyloidosis with injection of amyloid enhancing factor (AEF) together with casein in complete Freund's adjuvant, and non-amyloidogenic inflammation in the presence of AEF with injection of AEF together with LPS. Both A/J and SJL/J mice developed splenic amyloidosis 1 day after initiation of chronic inflammation in the presence of AEF. No amyloid deposits were detected during any of the other types of inflammation. Amyloidotic mice exhibited decreased amounts of SAA mRNA in liver and spleen concomitant with decreased amounts of SAA in serum. Alpha-I-acid glycoprotein mRNA was present in liver throughout the course of AEF accelerated amyloidosis, indicating that decreased SAA gene expression and AA fibril formation is not part of a general inhibitory effect of AEF on protein synthesis.

Animals↗
PubMed1988

Echinococcus multilocularis: relationship between persistent inflammation, serum amyloid A protein response and amyloidosis in four mouse strains.

LPS-hyporesponsive (C3H/HeJ) and LPS-sensitive (C57BL/6, CBA/J, C3H/HeSn) strains of mice were infected intraperitoneally with 50 alveolar hydatid cysts (AHC) to assess the effect of protracted severe inflammation on serum amyloid A protein (SAA) concentrations, splenic amyloid deposition, and pre- and postamyloidotic alterations in the splenic architecture. In general, the SAA concentrations in all the four mouse strains showed a moderate but steady increase throughout the course of infection. Splenic amyloid deposition commenced between 6 to 8 weeks postinfection (p.i.) when the SAA concentrations were relatively low and increased progressively until 12 weeks p.i. when 52 to 78% of the splenic parenchyma was obliterated. CBA mice which harbored the largest AHC throughout the 12-week course of infection showed the poorest SAA and amyloid responses; the situation was reversed in the C3H/HeSn strain. Histologically, most of the splenic follicles, during the stage of maximum amyloid deposition, appeared hypocellular. Their T-cell-dependent periarterial sinuses were either totally depleted of cells or contained plasma cells or myeloid cells. These results show that (a) there is no direct correlation between the intensity of inflammation, SAA concentrations, or amounts of amyloid deposition in either of the four mouse strains and (b) amyloidosis secondary to AHC infection differs from other experimental mouse models of amyloidosis in the magnitude of SAA elevation during the preamyloid phase.

Acute Disease↗
PubMed1988

Endotoxin-associated protein: interleukin-1-like activity on serum amyloid A synthesis and T-lymphocyte activation.

Bacterial endotoxins or lipopolysaccharides (LPS) elicit a variety of biologic activities in intact animals and various in vitro systems. LPS from most gram-negative bacteria have appeared to have similar biologic activities regardless of the species of origin or method of preparation of the LPS. More recent studies have suggested differences in the effects of protein-rich as opposed to protein-free LPS in inducing mitogenesis of lymphocytes from endotoxin-resistant C3H/HeJ mice. These studies examine other activities of endotoxin-associated protein (EAP), purified to less than 0.007% contamination with LPS, and demonstrate that this material has activity mimicking some of the effects of interleukin-1 (IL-1). EAP proved to be as potent as LPS in eliciting rises in concentrations of serum amyloid A (SAA) and was active in both endotoxin-sensitive (CF1) and endotoxin-resistant (C3H/HeJ) mice. In contrast to LPS, which mediates its SAA-inducing activity by release of an inducer (IL-1) from LPS-stimulated macrophages, EAP appeared to act directly to induce SAA production, in that incubation with macrophages failed to increase its activity. EAP also exhibited IL-1-like activity in the lymphocyte-activating factor assay when both CF1 and C3H/HeJ thymocytes and macrophages were tested. The lymphocyte-activating factor activity of EAP was not blocked by addition of polymyxin B. In addition, EAP exerted stimulatory activity on resting human T lymphocytes, costimulated with Sepharose-bound anti-CD3 monoclonal antibody 64.1, comparable to that observed with purified human monocyte IL-1. These studies indicate that proteins from procaryotic cells may act as cytokines for some eucaryotic cells.

Animals↗
PubMed1988

Comparison of in vivo effects of human recombinant IL 1 and human recombinant IL 6 in mice.

IL 1 and IL 6 share a number of biological activities, including induction of fever, neutrophilia and acute phase response, and IL 1 induces IL 6 production by fibroblasts and macrophages. Therefore, it was proposed that IL 6 mediates many of the activities of IL 1. To test this hypothesis in vivo, we assessed induction of IL 6 following IL 1 alpha administration to mice and tested IL 6 for radioprotection and induction of early (CSF) and late (fibrinogen and SAA) acute phase reactants. IL 1 alpha given to mice ip induced, in a dose dependent manner, detectable IL 6 in circulation, with maximal titers at 2-4 hrs. However, unlike IL 1 which is 10-1000 ng/mouse of human recombinant IL 6 did not result in increased survival of mice following lethal irradiation. In fact, such treatment given 20 hrs before LD50/30 doses of radiation resulted in reduced survival of mice. However, IL 6 augmented the radioprotective effect of IL 1. IL 1 in doses above 10 ng/mouse induced within 2 to 6 hrs a dose dependent increase in CSF in circulation, but IL 6 did not induce detectable levels of CSF at 2, 6 and 20 hrs after administration. Administration of IL 6 to mice produced a dose dependent increase in circulating fibrinogen and SAA. Similarly, administration of IL 1 resulted in much greater increases in levels of fibrinogen and SAA. Therefore, IL 1 is a more effective inducer of fibrinogen and SAA in mice than is IL 6. Although definitive conclusions concerning the relative roles for IL 1 and IL 6 in vivo will await availability of anti IL 1 and anti-IL 6 antibodies, our data do not support the suggestion that the above IL 1 effects can be attributed solely to IL 6.

Acute-Phase Reaction↗
PubMed1988

Dexamethasone modulation of LPS, IL-1, and TNF stimulated serum amyloid A synthesis in mice.

Three secretory products of the macrophage, interleukin 1 (IL-1), tumor necrosis factor/cachectin (TNF) and hepatocyte stimulating factor/interleukin 6 (IL-6) modulate liver protein synthesis during the acute phase response. Induction of serum amyloid A (SAA) synthesis is one of the most notable acute phase changes in liver proteins, with maximal SAA concentrations varying over a thousand-fold range in proportion to the amount of tissue injury and cell necrosis. Exogenous IL-1 and TNF induce SAA synthesis in vivo and in vitro, while exogenous IL-6 is a far less potent stimulus of in vivo SAA gene expression. Dexamethasone (DEX), a potent inhibitor of macrophage IL-1, TNF and IL-6 synthesis, was utilized to analyze the endogenous mediators of SAA synthesis in mice injected with lipopolysaccharide (LPS). DEX, although itself exhibiting the capacity to stimulate SAA synthesis to a limited extent, significantly reduced LPS induced SAA production. However, DEX did not reduce, but rather potentiated, IL-1 and TNF stimulated SAA production, indicating that these monokines do not require macrophage products to mediate their in vivo SAA inducer activity. SAA synthesis was observed in adrenalectomized mice, following administration of LPS, IL-1 and TNF, indicating that SAA induction by monokines is not secondary to corticosteroid release.

Animals↗
PubMed1987

Differential expression of the amyloid SAA 3 gene in liver and peritoneal macrophages of mice undergoing dissimilar inflammatory episodes.

The three active serum amyloid A (SAA) genes of mice, SAA 1, SAA 2, and SAA 3, are coordinately expressed in liver during acute and chronic inflammatory stimulation and experimental amyloidosis. The genes, primarily SAA 3, are also expressed extrahepatically. The apoprotein SAA 2 is the precursor of the amyloid A (AA) fibril protein that is deposited as insoluble fibrils extracellularly in spleen and other organs when amyloidosis occurs secondarily to inflammation. The exact cause of AA fibril formation is unknown. Amyloid enhancing factor is a high m.w. glycoprotein extracted from amyloidotic organs. Administration of amyloid enhancing factor alters experimental inflammation to bring about accelerated deposition of amyloid A fibrils first in spleen and later in other organs. In this study, hepatic and extrahepatic expression of the SAA genes were compared during accelerated amyloidosis relative to inflammation uncomplicated by amyloidosis. Differences in kinetics and pattern of SAA gene expression by resident peritoneal macrophages and liver were detected during four dissimilar inflammatory episodes. Macrophages expressed the SAA 3 gene solely, and to a greater extent in chronic than in acute inflammation. In accelerated amyloid induction, macrophage SAA 3 expression increased as SAA 1 and SAA 2 expression in liver decreased. However, alpha-1-acid glycoprotein expression remained elevated throughout the course of amyloid induction. The greatly increased expression of the SAA 3 gene by macrophages and decreased expression of the SAA 1 and SAA 2 genes in liver during amyloidosis, suggests that altered SAA gene expression may play a pathogenetic role in experimental amyloid deposition.

Amyloidosis↗
PubMed1987

Transcriptional regulation of genes encoding the acute-phase proteins CRP, SAA, and C3.

Inflammation or acute tissue injury results in a programmed change in the concentration of several plasma proteins. Among these proteins, two--C-reactive protein (CRP) and serum amyloid A protein (SAA)--increase up to 1000-fold after an acute-phase stimulus in humans and rabbits. To determine the mechanism for regulation of acute-phase gene expression, we examined changes in the rates of transcription and specific hepatic mRNA content for rabbit CRP, SAA, and some complement protein mRNA during an acute-phase response. Induction of a sterile inflammatory reaction with intramuscular injection of turpentine resulted in an increase in the hepatocellular content of CRP, SAA, C3, and factor B mRNA and the transcription of CRP, SAA, and C3 genes. These data suggest that the increase in CRP, SAA, and C3 serum concentrations observed during an acute-phase reaction is due to an increase in biosynthesis and is, at least in part, under transcriptional control.

Acute-Phase Proteins↗
PubMed1987

Comparison of the acute phase response of cultured Morris hepatoma 7777 cells and of rat hepatocytes.

Isolated Morris hepatoma cells (line 7777) or adult rat hepatocytes were cultured for 3 days and daily production of four plasma proteins was estimated in the cell media by rocket immunoelectrophoresis with monospecific antisera. Addition of cytokines from rat peritoneal macrophages to cultured hepatocytes or hepatoma cells augmented accumulation in the medium of two positive acute phase proteins: fibrinogen (FIB) and cysteine proteinase inhibitor (CPI). At the same time synthesis of alpha-fetoprotein (AFP) was inhibited in hepatoma cells but remained undetectable in hepatocytes. Rat macrophage cytokines typically depressed synthesis of albumin (ALB) in cultured rat hepatocytes but increased production of this protein by hepatoma cells.

Acute-Phase Proteins↗
PubMed1987

The acute phase response in gout.

We studied the acute phase response in gout. Oral temperature, white blood cell count and differential, platelet count, Westergren erythrocyte sedimentation rate (ESR), and serum levels of the acute phase reactants serum amyloid A protein (SAA) and C-reactive protein (CRP) were all elevated. The number of involved joints correlated with levels of ESR, SAA and CRP. CRP correlated with temperature, differential count, ESR and SAA. The acute phase response resolved rapidly with treatment.

Acute-Phase Proteins↗
PubMed1987

Tumor necrosis factor/cachectin is a less potent inducer of serum amyloid A synthesis than interleukin 1.

Serum amyloid A (SAA) gene expression is known to be induced by interleukin (IL-1). The time course of in vivo induction of SAA synthesis by IL-1 was found to vary according to dose, in that SAA concentration was maximal at 6 hours following lower doses of IL-1, but greater at 20 hours when higher (greater than 500 ng) doses were administered. Because of recent reports that recombinant human tumor necrosis factor/cachectin (TNF) is a pyrogen similar to IL-1, its efficacy as an inducer of SAA synthesis was analyzed. TNF was found to be at least 100 fold less potent that IL-1 on a weight basis in both C3H/HeJ and C57BL/6 mice. However, C3H/HeJ mice were found to be more sensitive than C57BL/6 mice to both IL-1 and TNF stimulated SAA production. The magnitude of the acute phase SAA response was therefore found to be a function of the type of inflammatory mediator and genetic factors in the host.

Animals↗
PubMed1987

Limited effects of recombinant human and murine interleukin 1 and tumour necrosis factor on production of acute phase proteins by cultured rat hepatocytes.

Albumin, fibrinogen, alpha 1-acid glycoprotein and cysteine proteinase inhibitor were determined by electroimmunoassay in the media of primary cultures of rat hepatocytes exposed to dialysed supernatants of rat, mouse and human macrophages or to recombinant human and murine interleukin 1 and tumour necrosis factor. Recombinant cytokines in the range of 1 to 1000 ng/ml caused only reduction of albumin synthesis and slight stimulation of alpha 1 acid glycoprotein production while crude preparations of macrophage cytokines elicited typical acute phase response. The results suggest that interleukin 1 or tumour necrosis factor are not likely the principal mediators responsible for the direct stimulation of normal rat hepatocytes to acute phase protein synthesis.

Animals↗
PubMed1985

Pretranslational modulation of acute phase hepatic protein synthesis by murine recombinant interleukin 1 (IL-1) and purified human IL-1.

During the acute phase response to tissue injury or inflammation, the concentration of several plasma proteins change. Previous work (29-34) suggested a role for interleukin 1 (IL-1) in the acute phase response. The availability of recombinant-generated mouse IL-1 prompted a study designed to directly test the function of IL-1 and its mechanism of action on hepatic synthesis of two positive acute phase proteins (serum amyloid A [SAA] and complement factor B), and a negative acute phase reactant (albumin). Intravenous injection of purified recombinant-generated murine-IL-1 into C3H/HeJ endotoxin-resistant mice induced a dose-dependent increase in SAA-specific hepatic messenger RNA (mRNA), and an increase in SAA plasma protein concentration. In primary murine hepatocyte cultures, both the recombinant IL-1 and highly purified human IL-1 induced a dose- and time-dependent, reversible increase in expression of the SAA and factor B genes, and a decrease in albumin gene expression. This regulation is pretranslational, since the kinetics and direction of change in specific mRNA for SAA, factor B, and albumin correspond to the changes in synthesis of the respective proteins. Moreover, the effect of IL-1 was specific, since actin gene expression was unaffected, and the IL-1 response was inhibited by antibody specific for IL-1. These data provide direct evidence that a single mediator, IL-1, can effect the positive and negative changes in specific hepatic gene expression characteristic of the acute phase response.

Acute-Phase Proteins↗
PubMed1985

Human serum amyloid A (SAA): biosynthesis and postsynthetic processing of preSAA and structural variants defined by complementary DNA.

To study structural variants of human serum amyloid A (SAA), an apoprotein of high-density lipoprotein, complementary DNA clones were isolated from a human liver library with the use of two synthetic oligonucleotide mixtures containing sequences that could code for residues 33-38 and 90-95 of the protein sequence. The SAA-specific cDNA clone (pA1) contains the nucleotide sequence coding for the mature SAA and 10 amino acids of the 18-residue signal peptide. It also includes a 70 nucleotide long 3'-untranslated region and approximately 120 bases of the poly(A) tail. The derived amino acid sequence of pA1 is identical with the alpha form of apoSAA1. A fragment of pA1 containing the conserved (residues 33-38) region of SAA also hybridized with RNA from human acute phase liver and acute phase stimulated, but not unstimulated, mouse and rabbit liver. In contrast, a fragment corresponding to the variable region hybridized to a much greater extent with human than with rabbit or murine RNA. Human acute phase liver SAA mRNA (approximately 600 nucleotides in length) directs synthesis of preSAA (Mr 14 000) in a cell-free translating system. In a Xenopus oocyte translation system preSAA is synthesized and processed to the mature Mr 12 000 product. The complete 18 amino acid signal peptide sequence of preSAA was derived from sequencing cDNA synthesized by "primer extension" from the region of SAA mRNA corresponding to the amino terminus of the mature product. Two other SAA-specific cDNA clones (pA6 and pA10) differed from pA1 in that they lack the internal PstI restriction enzyme site spanning residues 54-56 of pA1.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Widespread occurrence of AP in amyloidotic tissues. An immunohistochemical observation.

Plasma (P)-component of amyloid (AP or SAP), while not an integral part of the amyloid fibril, has been considered to be intimately associated with virtually every different type of amyloid. In the present study, we evaluated the distribution of AP in the organs frequently involved in two forms of human systemic amyloidosis (AA and AF) and in mouse AA amyloidosis, by use of immunohistochemistry with anti-AP. Although the amyloid deposits generally showed moderate reactions with anti-AP, they were not always clearly distinguished from the surrounding non-amyloid tissue elements which often stained as well. The basement membrane often showed even stronger reaction to anti-AP than the adjacent amyloid deposits, and liver sections demonstrated such a high overall reaction to anti-AP that the anti-AP reaction on the amyloid deposits was often obscurred. The present results suggest that the binding between AP and the amyloid fibril may not be monospecific, that AP by this technique occurs rather widely throughout the body, and therefore that anti-AP may not be considered as specific a marker for amyloid deposits in immunohistochemical and perhaps other studies as well.

Amyloid↗
PubMed1985

Lowered prealbumin levels in patients with familial amyloid polyneuropathy (FAP) and their non-affected but at risk relatives.

Amyloid fibrils in familial amyloid polyneuropathy, the familial (AF) form of systemic amyloidosis, are composed of the monomeric unit (14,000 MW) of prealbumin molecules. By radioimmunoassay, the serum level of prealbumin was measured in 25 patients from 12 different kinships with this dominantly inherited form of amyloidosis and 56 unaffected, but at risk, relatives from two of the kinships. Results were compared to prealbumin levels in normal individuals and patients with primary (AL) and secondary (AA) forms of systemic amyloidosis. Significantly lowered prealbumin levels were found in the AF patients (149.2 micrograms/ml) and their at risk relatives (169.0 micrograms/ml) when compared to normal individuals (232.9 micrograms/ml), AL patients (221.9 micrograms/ml) and AA patients (211.7 micrograms/ml). No abnormality was found in levels of retinol binding protein (RBP), which is carried by prealbumin, in the serum of either the AF patients or their relatives. The depressed prealbumin levels may indicate a structural variant molecular form, an extra hepatic synthesis or an abnormality in catabolism of this protein that is present prior to the clinical or histopathologic onset of the AF disease.

Amyloidosis↗