Human serum amyloid A has cytokine-like properties

Human serum amyloid A (SAA) proteins are a group of 12-14 kDa apolipoproteins found predominantly in the high-density lipoprotein (HDL) fraction of plasma. Several functions have been proposed for SAA, but its primary physiological function remains elusive. In this report, we used the monocytic cell line THP-1 to investigate whether recombinant SAA1 (rSAA) or the HDL-rSAA protein complex can affect the capacity of these cells to produce inflammatory cytokines in vitro. Incubation of rSAA, plasma HDL (which contains < or = 30 microg/ml of SAA) or HDL-rSAA complex with THP-1 cells induced synthesis of IL-1beta, IL-1ra and sTNFR-II protein and mRNA. The induction of cytokine synthesis was not due to endotoxin contamination since the effect was abrogated by protein denaturation. The rSAA and HDL-rSAA complex did not induce detectable levels of IL-6 or TNFalpha protein or mRNA. In contrast 10 microg/ml LPS stimulated secretion of the inflammatory cytokines, IL-1beta, IL-6 and TNFalpha, as well as IL-1ra and sTNFR-II from THP-1 cells. We confirmed that rSAA has chemoattractant properties in vivo, by subcutaneous injections into mice and examined the histology of the injection site at 72 h, however, the HDL-rSAA complex has a substantially reduced effect.     

Enhanced inflammatory response to coronary angioplasty in patients with severe unstable angina

BACKGROUND: Systemic markers of inflammation have been found in unstable angina. Disruption of culprit coronary stenoses may cause a greater inflammatory response in patients with unstable than those with stable angina. We assessed the time course of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) after single-vessel PTCA in 30 patients with stable and 56 patients with unstable angina (protocol A). We also studied 12 patients with stable and 15 with unstable angina after diagnostic coronary angiography (protocol B). METHODS AND RESULTS: Peripheral blood samples were taken before and 6, 24, 48, and 72 hours after PTCA or angiography. In protocol A, baseline CRP, SAA, and IL-6 levels were normal in 87% of stable and 29% of unstable patients. After PTCA, CRP, SAA, and IL-6 did not change in stable patients and unstable patients with normal baseline levels but increased in unstable patients with raised baseline levels (all P<0.001). In protocol B, CRP, SAA, and IL-6 did not change in stable angina patients after angiography but increased in unstable angina patients (all P<0.05). Baseline CRP and SAA levels correlated with their peak values after PTCA and angiography (all P<0.001). CONCLUSIONS: Our data suggest that plaque rupture per se is not the main cause of the acute-phase protein increase in unstable angina and that increased baseline levels of acute-phase proteins are a marker of the hyperresponsiveness of the inflammatory system even to small stimuli. Thus, an enhanced inflammatory response to nonspecific stimuli may be involved in the pathogenesis of unstable angina.     

The primary structure of rabbit serum amyloid A protein isolated from acute phase serum

Serum amyloid A (SAA) protein, a sensitive acute phase protein and the precursor of protein AA in secondary amyloid, was purified from pooled acute phase rabbit serum using two different methods: isolation of protein SAA directly by octyl-Sepharose chromatography of total serum, and dissociation and isolation of apoSAA from acute phase high density lipoprotein (HDL). The protein SAA fraction obtained was further purified using gel filtration and ion exchange chromatography. Rabbit protein SAA has 104 amino acid residues, like human SAA, and has a partially blocked N terminus. The highly conserved region from position 33 to position 63 found in SAA from all species studied was confirmed also in rabbit SAA. No microheterogeneities were observed. The amino acid sequence showed extensive N-terminal homology with the rabbit amyloid A protein, except for the microheterogeneity in position 12 in protein AA. It also showed identical amino acid sequence with that deduced from the rabbit cDNA clone pSAA 55. Complete homologies were found with clone SAA 2, except for positions 22 and 78, clone SA8-1, except for positions 22 and 79 and clone SA7-3, except for position 22. This pSAA 55/SA7-3/SA8-1/SAA2-like protein was the only SAA isotype found both in total serum and in the HDL fraction. Isotypes corresponding to other SAA-like genes could not be found in this pool of acute phase rabbit sera.     

Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice

In vitro, IL-6 is the main inducer of the human C-reactive protein (CRP) gene, and IL-1 and steroids can enhance this effect. However, in mice, IL-6 is necessary but not sufficient for induction of the human CRP transgene, and testosterone is required for its constitutive expression by males. To examine the relative contributions of testosterone and IL-6 in the regulation of CRP gene expression, we produced CRP-transgenic (CRPtg), IL-6-deficient (IL-6-/-) mice. Male CRPtg/IL-6-/- mice expressed CRP constitutively, but CRP levels were not increased after injection of LPS. However, acute-phase CRP levels were attained after injection of IL-6. In contrast, female CRPtg/IL-6-/- mice did not express CRP constitutively or after administration of LPS, IL-6, IL-1, or IL-6 plus IL-1. Like males, testosterone-treated CRPtg/IL-6-/- females expressed CRP constitutively, and their transgene responded to injection of IL-6. The endogenous acute-phase protein serum amyloid P (SAP) was expressed constitutively equally by male and female IL-6-/- mice, responded minimally to LPS, and did not respond to either IL-6 or IL-1 alone. Acute-phase levels of SAP were induced in IL-6-/- mice by injection of IL-6 together with IL-1 or LPS. We conclude that in vivo, both constitutive and IL-6-dependent acute-phase expression of the CRP transgene require testosterone. In contrast, testosterone is not required for expression of the SAP gene, which requires IL-1 plus IL-6 for acute-phase induction.     

Occurrence of amyloid-related serum proteins in patients with benign monoclonal gammopathy

The serum protein SAA, which is related to the amyloid fibril protein AA, was detected by double immunodiffusion using anti-protein AA antiserum. The SAA level was elevated in 16 to 32 patients with benign monoclonal gammopathy (BMG). In addition, two BMG sera reacted with an antiserum to amyloid fibril protein of immunoglobulin light-chain type, V lambdaI (EF), and one reacted with antiamyloid protein VlambdaV (AR). The reactivity of the BMG sera with antisera to the various amyloid fibril proteins was strikingly similar to that of 35 sera from patients with myelomatosis. In the age group of 50--70 years the proportion of SAA-positive sera in BMG (53%) and myelomatosis (56%) was strikingly higher than that of the normal controls (5%). In older subjects (70--90 years), however, the frequency of SAA in BMG or myelomatosis, although increased (53%--54%), was not significantly greater than that of a control group of apparently healthy individuals (44%).     

Ubiquitin profile in inflammatory leukocytes and binding of ubiquitin to murine AA amyloid: immunocytochemical and immunogold electron microscopic studies

Lysosomes in activated murine monocytoid cells have been implicated in AA amyloid formation. The pathophysiology of this process is not well understood. Previous studies into the nature of the relationship between ubiquitin (UB), possessing intrinsic amyloid enhancing factor (AEF) activity; serum amyloid A (SAA), the precursor protein of AA amyloid; and activated monocytoid cells have indicated a temporal and spatial relationship between these proteins and tissue AA amyloid deposits. To extend these findings, we have examined murine peritoneal leukocytes and splenic tissues during the early amyloid deposition phase by immunocytochemical and immunogold electron microscopic methods using monospecific anti-ubiquitin and anti-mouse AA amyloid antibodies. We show here enrichment of endosome-lysosome-like (EL) vesicles in the activated monocytoid cells with UB and SAA, and the presence of UB-bound AA amyloid fibrils in the EL vesicles, perikarya, and interstitial spaces. The importance of these findings is emphasized by the fact that activated monocytoid cells, containing UB in the EL vesicles, sequester and eventually localize SAA in their EL vesicles, and that UB binds to the EL-contained AA amyloid fibrils. These findings may also have functional consequences for studies on the role of EL and UB in amyloidogenesis.     

Intracerebroventricular injection of anti-Fas activates the hypothalamus-pituitary-adrenal axis and induces peripheral interleukin-6 and serum amyloid A in mice: comparison with other ligands of the tumor necrosis factor/nerve growth factor receptor superfamily

Fas is a receptor of the tumor necrosis factor (TNF)/ nerve growth factor (NGF) receptor superfamily that mediates apoptosis and some inflammatory changes. As the central administration of TNF is known to activate the hypothalamus-pituitary-adrenal axis (HPAA) and to induce peripheral responses including induction of serum interleukin (IL)-6 and serum amyloid A (SAA), we investigated the effects of intracerebroventricular (i.c.v.) administration of agonist anti-Fas monoclonal antibody Jo2. Centrally administered anti-Fas (1 microg/mouse, i.c.v.) induced elevated levels of corticosterone, IL-6, and SAA comparable to those observed after i.c.v. administration of recombinant murine TNF. On the other hand, administration of murine NGF did not elevate serum corticosterone or IL-6, but induced SAA. Thus, Fas can trigger a centrally mediated anti-inflammatory response (HPAA activation) and induce a peripheral acute-phase response comparable to that induced with TNF, whereas NGF induces only acute-phase proteins.     

Mouse serum amyloid A (SAA) proteins isolated by two-dimensional electrophoresis: characterization of isotypes and the effect of separate and combined administrations of cytokines, dexamethasone and lipopolysaccharide (LPS) on serum levels and isotype distribution

Hydrophobic interaction chromatography and two-dimensional electrophoresis were used to isolate and characterize mouse SAA, and to study the in vivo effect of separate or combined administrations of cytokines, dexamethasone (DEX) and LPS on mouse SAA. Four SAA spots containing partial amino acid sequence in accordance with mouse apoSAA and apoSAA2/SAA(SJL/J) pI 5.9 were demonstrated in serum. One of these proteins represents a previously undescribed, acidic acute-phase mouse SAA protein. Both DEX and interferon-gamma (IFN-gamma) proved to be capable of increasing SAA serum levels. In contrast to what has been shown in previous in vivo studies, administration of IL-6 did increase the SAA levels to nearly the same magnitude as IL-1, and the effect of IL-6 and LPS on SAA production was not significantly altered by the addition of DEX. Irrespective of the inflammatory stimuli that was administered, a non-selective production of SAA1 and SAA2 was observed in most groups, including the group that received IL-6. The results illustrate that data obtained about mouse SAA are highly dependent on which models, isolation and identification methods are used.     

1998 Annual Meeting of the Society of Orthopedics and Athletic Traumatology (GOTS)

BACKGROUND: Elevation of acute phase proteins [C-reactive protein (CRP) and serum amyloid type A (SAA)] has been demonstrated in unstable angina with an adverse clinical prognosis. HYPOTHESIS: The study was undertaken to determine the effect of angioplasty on the levels of SAA and the correlation with postangioplasty restenosis. METHODS: In a university-affiliated tertiary medical center, a prospective case study was undertaken in 55 patients who underwent successful percutaneous transluminal coronary angioplasty (PTCA) of a single coronary lesion for angina pectoris. Three groups of patients were clinically characterized according to Braunwald's classification of anginal syndrome: Group A: class III; Group B: class I; Group C: stable angina. Serum amyloid type A was measured by an ELISA method before PTCA and after 24 h, 1, and 3 months. Patients were followed clinically for 12 months. A thallium stress perfusion scan was performed 3 months after PTCA and coronary angiography was repeated in patients with an abnormal thallium perfusion scan. RESULTS: Serum amyloid type A levels > 100 micrograms/ml could identify Group A patients with a high sensitivity and specificity (r = 0.85 and 0.86, respectively). Of the patients studied, 75% increased their SAA level 24 h after angioplasty. An increase of SAA by > 100% was associated with an increased risk of restenosis, with a relative risk of 6.4 (p < 0.05). CONCLUSION: Increased levels of SAA characterize patients with unstable angina pectoris with a high specificity and sensitivity. Levels of SAA that increase > 100% 24 h after angioplasty may serve as a marker of restenosis.     

Hyperthyroidism. Etiology, physiopathology, diagnosis, evolution, treatment]

Serum amyloid A (SAA) is an acute-phase reactant whose level in the blood is elevated to 1000-fold as part of the body's responses to various injuries, including trauma, infection, inflammation, and neoplasia. As an acute-phase reactant, the liver has been considered to be the primary site of expression. However, limited extrahepatic SAA expression was described in mouse tissues and in cells of human atherosclerotic lesions. Here we describe nonradioactive in situ hybridization experiments revealing that the SAA mRNA is widely expressed in many histologically normal human tissues. Expression was localized predominantly to the epithelial components of a variety of tissues, including breast, stomach, small and large intestine, prostate, lung, pancreas, kidney, tonsil, thyroid, pituitary, placenta, skin epidermis, and brain neurons. Expression was also observed in lymphocytes, plasma cells, and endothelial cells. RT-PCR analysis of selected tissues revealed expression of the SAA1, SAA2, and SAA4 genes but not of SAA3, consistent with expression of these genes in the liver. Immunohistochemical staining revealed SAA protein expression that co-localized with SAA mRNA expression. These data indicate local production of the SAA proteins in histologically normal human extrahepatic tissues.     

Involvement of an SAF-like transcription factor in the activation of serum amyloid A gene in monocyte/macrophage cells by lipopolysaccharide

Serum amyloid A (SAA) has been linked to atherosclerosis because of its ability to remodel high-density lipoprotein by the depletion of apolipoprotein A1, its ability to bind cholesterol, and its presence in the atherosclerotic plaques of coronary and carotid arteries. In the present study, we investigated the induction mechanism of SAA gene in THP-1 monocyte/macrophage cells which play a critical role in the development of atherosclerotic fatty streak and plaque formation. We and others have shown that SAA gene is induced in monocyte/macrophage cells by lipopolysaccharide (LPS). By promoter function analysis, we show that the SAA promoter sequence between -280 and -226 can confer LPS responsiveness. Gel electrophoretic mobility shift assay detected an induced DNA-binding activity in these cells in response to LPS. Characterization of the DNA-binding protein by UV cross-linking, Southwestern blot, and antibody ablation/supershift assays revealed that it is similar to a recently reported nuclear factor designated SAF. These results demonstrated that LPS-mediated SAA gene induction in monocyte/macrophage cells is primarily due to the induction of SAF activity.     

Evolution of the serum amyloid A (SAA) protein superfamily

The serum amyloid A (SAA) superfamily comprises a number of genes and proteins characterized from a range of mammalian species. The majority of members described to date are dramatically induced during the acute-phase response, suggesting an important short-term beneficial role in the response to tissue injury and inflammation. However, important disease associations have also been proposed for certain SAAs during chronic inflammation. The nomenclature of many of the superfamily members has been the result of comparisons with previously reported sequences implying disease association and/or functional relatedness between such members. The evolutionary relationships of the SAA superfamily members have been investigated by comparisons at both the amino acid and the nucleotide level. The results indicate that all members of the superfamily within a species have been undergoing concerted evolution. This has important implications in ascribing functions and disease associations to individual SAA superfamily members and indicates that designations should not be based on the extent of amino acid identity alone but should be made only following direct experimental observation of the proteins themselves.     

Increased acute-phase response and renal amyloidosis in aged CD2-fas-transgenic mice

We previously demonstrated that increased Fas expression in T cells of aged CD2-fas transgenic (Fas-Tg) CD-1 mice results in an increased immune response and T cell apoptosis. Surprisingly, despite prevention of T cell immune senescence, the average life span of Fas-Tg mice is comparable with that of nontransgenic (non-Tg) mice. Histopathologic evaluation of tissue sections showed that nearly 50% of the aged (>18-mo-old) Fas-Tg mice developed renal amyloid A amyloidosis, whereas no amyloid deposition was observed in aged non-Tg mice. The amyloid A deposition was observed primarily in glomeruli by using immunohistochemical stains and electron microscopy. The full-length amino acid coding sequence of serum amyloid A2 cDNA in CD-1 mice was identical to that of amyloid A amyloidosis-susceptible BALB/c mice. Although there was no significant difference in steady-state serum amyloid A level in the serum of aged non-Tg and Fas-Tg mice, challenging mice with staphylococcal enterotoxin B resulted in significantly higher serum levels of serum amyloid A on day 2 and IL-6 on days 1 and 2 and a higher magnitude of weight loss on day 7 in aged Fas-Tg mice compared with young mice. These parameters, at the indicated time points, were equivalent between young and aged non-Tg mice. Taken together, our data suggest that prevention of T cell senescence in Fas-Tg mice may be a factor in induction of an excessive acute-phase response triggered by T cell activation. The Fas-Tg mice are a novel model for understanding the immunologic mechanisms leading to secondary amyloidosis.     

Effects of methyl palmitate on cytokine release, liver injury and survival in mice with sepsis

The effects of methyl palmitate (MP), a known inhibitor of Kupffer cells, were studied in a model of polymicrobial sepsis induced in CD-1 mice by cecal ligation and puncture (CLP). The inhibition of Kupffer cells by pretreatment with MP was shown by the reduced phagocytosis, the production of tumor necrosis factor (TNF) and interleukin-6 (IL-6) after lipopolysaccharide (LPS) challenge. The reduced activation of Kupffer cells resulted in lower levels of inflammatory products after CLP. TNF and IL-6 were significantly reduced in serum 2 h and 24 h respectively after CLP, interleukin-1 beta (IL-1 beta) was reduced in liver 4 h after CLP, nitric oxide (NO) and serum amyloid A (SAA) were significantly reduced 8 and 24 h respectively after CLP. Liver toxicity was significantly reduced in MP-treated mice and survival was significantly prolonged at all intervals, reaching 45% after six to ten days compared with 3% in control mice. These findings suggest that Kupffer cells play an important role in liver damage and survival in sepsis.     

Increased circulating cytokine receptors and ex vivo interleukin-1 receptor antagonist and interleukin-1beta production but decreased tumour necrosis factor-alpha production after a 5-km run

BACKGROUND: The purpose of this study was to examine the effect of a 5-km run on blood leucocytes, acute-phase proteins and cytokines. In addition, cytokines were measured in the supernatants from whole-blood cell cultures incubated with lipolysaccharide (LPS). METHODS: Ten healthy, recreational trained, athletes (three women, seven men) volunteered for this investigation. Samples were drawn just before, immediately after and at 3 h, at 24 h and at 48 h after the race. RESULTS: Exercise induced a transient leucocytosis (P = 0. 0002) and a mild acute-phase reaction with increase in plasma C-reactive protein (CRP) (P = 0.0115) but not in serum amyloid A (SAA) concentrations. Although plasma interleukin 6 (IL-6) was undetectable and soluble interleukin-1 receptor type II (IL-1sRII) remained unchanged, interleukin-1 receptor antagonist (IL-1ra) concentrations were elevated directly after the race with a further increase at 3 h (P < 0.0001). Soluble tumour necrosis factor (TNF) receptors were increased immediately after the run, but the effect was more marked for sTNFr p55 (two-fold increase; P < 0.0001) than for sTNFr p75 (1.16-fold increase; P = 00007). In cell cultures, the LPS-induced release of the inflammatory cytokines doubled for IL-1beta (P < 0.0001) and for IL-1ra (P < 0.0001). In contrast, TNF-alpha production decreased after the run, and a nadir was reached at 24 h (P < 0.0001). CONCLUSION: These results suggest that a 5-km run elicits both the production of acute-phase mediators (leucocytosis and elevation of CRP) and anti-inflammatory counter-regulation as judged by the increase in circulating concentrations of IL-1ra, sTNFr p55, and sTNFrp75 and down-regulation of LPS-stimulated TNF-alpha production.     

Mutations of Arabidopsis in potential transduction and response components of the phototropic signaling pathway

IL-1 plays an important role in the pathophysiologic responses to infection and inflammation, in part by mediating its own production and that of other proinflammatory cytokines. However, the relative contribution of IL-1 alpha and IL-1 beta to the inflammatory response has not been well clarified. Using IL-1 beta-deficient (IL-1 beta -/-) mice, we investigated the specific role of IL-1 beta in the in vivo and in vitro response to LPS. No differences between IL-1 beta +/+ and IL-1 beta -/- mice were observed in circulating levels for IL-1 alpha, IL-6, or TNF-alpha after the systemic administration of either a low (5 micrograms/kg) or high (5 mg/kg) dose of LPS. IL-1 beta -/- mice also had a normal response to LPS in terms of activation of the hypothalamus-pituitary-adrenal axis, hypoglycemia, serum amyloid A production, and anorexia. IL-1 beta -/- mice were normally sensitive to the lethal effect of LPS and were protected against LPS toxicity when pretreated with low-dose LPS. However, in vitro, peritoneal macrophages from IL-1 beta -/- mice stimulated with LPS produced significantly less IL-1 alpha than macrophages from IL-1 beta +/+ mice (p < 0.05). No differences in IL-6 or TNF-alpha synthesis were observed between macrophages from IL-1 beta +/+ and IL-1 beta -/- mice. In summary, our results suggest that either IL-1 beta is not essential for the in vivo systemic response to LPS or that its role can be fulfilled by other cytokines with overlapping activities.     

Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6

Cachexia and the acute-phase response are common manifestations of inflammation and are presumed to be the product of increased synthesis and release of cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6). IL-1 receptor blockade has been previously shown to attenuate the weight loss, anorexia and acute-phase protein responses associated with a turpentine abscess. However, IL-1 receptor blockade was also associated with a reduced plasma IL-6 response, suggesting that the benefit achieved by IL-1 receptor blockade may be mediated by reduced systemic IL-6 production. To gain a better understanding of the role of IL-6 in this model of inflammation, C57BL/6 mice were passively immunized with either a monoclonal anti-IL-6 antibody (20F3), an anti-IL-1 type I receptor monoclonal antibody (35F5), a non-immune rat IgG, or a combined therapy of 35F5 and 20F3, before receiving a sterile turpentine abscess. IL-6 or IL-1 receptor blockade equally spared body weight and food intake. Compared to IL-1 receptor blockade, passive immunization against IL-6 further reduced the hepatic acute-phase protein response, as represented by serum amyloid P and complement 3. Combined blockade of IL-6 and IL-1 receptor did not result in a further sparing of body weights or improvement of food intake. These results confirm that IL-1 contributes to host cachexia and the acute-phase response following a turpentine abscess, but also show that these actions are dependent upon an IL-6 response. We conclude that the influence of IL-1 on cachexia and the acute-phase response is mediated, at least in part, through IL-6 and, thus, IL-6 may play a pivotal role in the cachexia and acute-phase response to inflammation.     

Low levels of sequence divergence in rock wallabies (Petrogale) suggest a lack of positive directional selection in SRY

We report a case of a 35-year-old man with secondary amyloidosis chiefly involving the kidney and heart. The patient showed severe proteinuria and ischemic heart damage and had hepatic adenoma at the age of 33. Biopsy specimens from the kidney, heart, stomach and rectum showed extensive deposition of amyloid. After the surgical resection of a 300-gram hepatic adenoma, highly elevated c-reactive protein (CRP) levels decreased and the serum amyloid A (SAA) level was completely normalized. Normal liver cells were immunostained with rabbit anti-SAA antibody, but the cells in adenoma tissue and kidney were not. Electron microscopic examination revealed extracellular deposition of amyloid fibrils in the hepatic adenoma and kidney tissue. The concentration of tumor necrosis factor-alpha (TNF-alpha) (312 pg/mg tissue protein) was 7-fold higher in adenoma tissue than in normal liver tissue. Moreover, SAA (2.8 ng/mg tissue protein) was 2-fold higher in normal liver tissue than in adenoma tissue. Since TNF-alpha has been known to induce SAA production in target cells, the present results suggest that the hepatic adenoma produced TNF-alpha, which then caused mainly secondary amyloidosis in the kidney and heart. Currently, 2 years after surgical resection, urinary excretion of protein has been markedly reduced (from 3.5 to 0.8 g/day) and renal and cardiac functions are normal without specific medical treatment.     

Dietary soybean protein compared with casein retards senescence in the senescence accelerated mouse

The effects of replacing dietary casein with soybean protein on mean life span, mean life span of the last one-tenth of a group, grading scores of senescence and deposition of senile amyloid were investigated in senescence accelerated mice (SAM-P/1) compared with a control strain (SAM-R/1). SAM-R/1 mice fed the soybean protein-containing diet had mean life spans of 618 +/- 42 d (males) and 578 +/- 62 d (females), 58% (males) and 44% (females) longer than those of corresponding casein fed mice (P < 0.01). Similarly, in SAM-P/1 mean life-spans were 265 +/- 16 d (males) and 307 +/- 23 d (females) in the soybean diet group, 27% (males) and 30% (females) longer than in the casein diet groups (P < 0.01). The mean life span of the last one-tenth of each group fed soybean protein was significantly longer than the corresponding group fed casein. In SAM-R/1 mice, pathological studies revealed that severe secondary amyloid deposition (amyloid A protein) in the kidneys, spleen, stomach and liver was significantly suppressed, in males only, by replacing casein with soybean protein (P < 0.01). The occurrence of contracted kidneys caused by the infiltration of amyloid A protein was suppressed in SAM-R/1 mice fed the soybean protein-containing diet (P < 0.05). The deposition of senile amyloid in SAM-P/1 mice with aging was retarded by replacing casein with soybean protein (P < 0.01). These results indicate that dietary protein source is important in modulating the advance of senescence in SAM mice.     

Effect of serum amyloid A on selected in vitro functions of isolated human neutrophils

Serum amyloid A (SAA) is an acute phase reactant whose levels in the blood rise as part of the body's response to stress and inflammation. Previous studies have suggested that SAA may carry an anti-inflammatory potential. We evaluated the effects of SAA on human neutrophils activated by N-formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. At concentrations higher than 10 microg/mL, SAA inhibited neutrophil myeloperoxidase (MPO) release. This effect was located in the N-terminal--that is, amino acid residues 1-14--of the SAA molecule. Directed neutrophil migration was inhibited at the same SAA concentrations. Several amino acid residues (1-14, 15-104, 83-104) contributed to this effect. Neutrophil O2- production was inhibited at low concentrations of SAA (0.1 to 1 microg/ml) and was stimulated at concentrations higher than 50 microg/mL. Neutrophil O2- production induced by phorbol myristate acetate (PMA) and O2- generated by the xanthine-xanthine oxidase reaction were not affected by SAA. These results add to previous data suggesting that SAA, at concentrations recorded in the serum during inflammation, modulates neutrophil function; thus it may play a role in the down-regulation of the inflammatory process.