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(The FASEB Journal. 2001;15:2241-2246.)
© 2001 FASEB

Expression of serum amyloid A genes in mouse brain: unprecedented response to inflammatory mediators

PAMELA C. TUCKER1 and GEORGE H. SACK JR*2

The Johns Hopkins University School of Medicine, Departments of Medicine,
* Biological Chemistry, and
* Pediatrics, Baltimore, Maryland 21205, USA

2Correspondence: Department of Biological Chemistry, Physiology 615, The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA. E-mail: gsack{at}jhmi.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Serum amyloid A (SAA) proteins were originally identified as prominent acute-phase serum proteins synthesized predominantly by hepatocytes. These small proteins are remarkably lipophilic, and we have sought evidence for their synthesis in mouse brain. RT-PCR showed constitutive expression of the murine SAA1 gene in the brains of normal BALB/cJ mice. After intracerebral inoculation with Sindbis virus, these mice predictably increase brain expression of tumor necrosis factor {alpha} (TNF-{alpha}), interleukin 1ß (IL-1ß), and IL-6. However, brain SAA1 expression fell after injecting either virus or control saline and remained low despite increases in TNF-{alpha} and IL-6, which are known to induce its expression in hepatocytes. Our data thus show that expression of the murine SAA1 gene has different, unprecedented control in mouse brain, suggesting that the protein itself may have a different physiological role there.—Tucker, P. C., Sack, G. H., Jr. Expression of serum amyloid A (SAA) genes in mouse brain: unprecedented response to inflammatory mediators.


Key Words: inflammation • neuroimmunology • acute-phase reactants • gene regulation • SAA


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
SERUM AMYLOID A (SAA) proteins were identified originally as components of normal serum (1 , 2) ; fragments of SAA proteins are found in the fibrils in secondary amyloid disease (3) . Accumulation of these amyloid fibrils leads to progressive organ failure and death. Although serum levels of SAA are generally low, they can rise rapidly in 24 h as part of the acute-phase response (including exposure to bacterial lipopolysaccharide [LPS]) in humans and mice (4) . The increased serum levels of SAA reflect stimulated transcription in the liver; proximal mediators include tumor necrosis factor (TNF-{alpha}) and interleukins 1 and 6 (IL-1, IL-6) (5 6 7) . In mice after acute-phase stimulation with LPS, total hepatic SAA mRNA levels rise rapidly and remain high for 36 h, after which they return to baseline (4 , 8) .

Despite their prominent induction during the acute-phase response and several proposed roles in vivo and in vitro, the primary physiological function(s) for SAA proteins remain unclear. SAA proteins are small (104 amino acids in humans, 103 in mice) and well conserved in evolution (9) . They are lipophilic (10 , 11) and poorly soluble in aqueous solution. SAA binds as a lipoprotein to the high density lipoprotein (HDL)3 fraction of serum, altering delivery of cholesterol-laden HDL to hepatocytes, macrophages, and other cells (12 13 14) . Cholesterol binding is mediated by amino acids 1–18 of acute-phase SAA (15) . At least one member of the SAA protein family is an autocrine stimulator of collagenase in inflamed synovial cells (16 17) .

Because SAA proteins bind cholesterol, show lipid solubility, and are prominent in inflammation, we have sought evidence for their synthesis in the brains of mice where many details of inflammatory responses to experimental infections have been studied. We used RT-PCR to evaluate SAA mRNA production in brains of normal mice and in response to a viral infection. We have found constitutive SAA gene expression in normal murine brain as well as a remarkable decrease in its expression during viral infection despite the presence of inflammatory mediators (TNF-{alpha}, IL-6, and IL-1ß).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Virus, infection, and treatment of mice
Sindbis virus (strain AR339) was grown and titered on BHK-21 cells. Intracerebral inoculation of AR339 leads to mononuclear cell inflammation and pathological changes consistent with encephalitis in adult mice brains, yet the mice are asymptomatic and the virus is cleared after 8 days (18) . Virus-free BALB/cJ mice (Jackson Laboratory, Bar Harbor, ME) were inoculated intracerebrally with 1000 plaque-forming units of virus in 0.03 ml of Hanks’ balanced salt solution (HBSS). At each time point after infection, three mice were killed by cervical dislocation, and brains and livers were removed and frozen immediately at -70°C.

Detection of SAA and cytokines by RT-PCR
mRNA was detected by RT-PCR as described (19) . Cellular RNA was extracted from frozen homogenized brain or liver with RNAZOL (Tel-Test, Inc., Friendswood, TX) and primed with oligo(dT). Reverse transcription was carried out with avian myeloblastosis virus reverse transcriptase (Boehringer Mannheim, Indianapolis, IN).

The PCR used primers whose sequences are conserved between expressed murine SAA genes (20) to amplify a 312 nucleotide product that crossed splice sites to avoid confusion between amplification from cDNA and genomic DNA (see Table 1 ). Different numbers of PCR cycles were performed to ensure that amplification was occurring in the linear range. PCR using negative controls (water used instead of RNA for synthesis) and a positive control (cDNA for glyceraldehyde-3-phosphate dehydrogenase) were included in every run. Serial dilutions of the positive control were amplified at 25, 30, and 35 cycles, generating a standard curve to ensure a fixed relationship between initial RNA input and densitometric readout.


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  		Table 1. Sequences of primers used for PCR amplification of mRNAs, product sizes, and sequences of the probes used for Southern blot analysis of PCR products

A portion of the PCR reaction was electrophoresed through a 1.2% agarose gel and transferred to nylon (Amersham, Arlington Heights, IL). An oligonucleotide probe (Table 1) internal to the PCR primers was labeled with 32P-ATP using T4 polynucleotide kinase and then used for Southern blot analysis. Radioactivity of the bands on the autoradiograms was estimated by laser scanning densitometry (Molecular Dynamics, Sunnyvale, CA). The relative intensity of each mRNA band was divided by the intensity of the autoradiogram band for the internal positive control to determine the relative amount of mRNA. All studies were performed in duplicate.

Sequencing of RT-PCR products
The product of 30 amplification cycles was run on a 2% Nu-sieve agarose gel (FMC Bioproducts, Rockland, ME). The gel was stained with ethidium bromide and the prominent band was cut from the gel. DNA was eluted from the gel slice using a Qiagen column. Sequencing of both strands was performed using the original PCR primers and an Applied Biosystems (Foster City, CA) sequencer.


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
SAA primers produce a product from brain homogenates using RT-PCR
Figure 1 shows that RT-PCR produced the expected 312 nucleotide product using RNA from normal murine brain as a template in each of 44 brains that had been frozen, as described, for other studies. Finding consistent SAA expression in samples from unstimulated, uninfected mice led to further characterization.



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  		Figure 1. Ethidium bromide staining of RT-PCR products synthesized using SAA primers on samples from two sets of 22 normal mouse brains and electrophoresed on a 1% agarose gel. Each sample showed a single band (appearing broad because the lanes in this gel were intentionally overloaded) and sequencing showed only the sequence presented in Fig. 2 .

The RT-PCR product corresponds to murine SAA1
Figure 2 shows the sequence of the RT-PCR product. Only a single sequence was found, corresponding precisely to the transcript expected from the murine SAA1 gene (20) . Splice junctions are present, consistent with this being an authentic transcript containing sequence information from exons 2–4 of the chromosomal gene (20) as delimited by the primer sequences.



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  		Figure 2. Nucleotide sequence of RT-PCR product from mouse brain using SAA primers shown in Table 1 . Sequencing from each direction showed no deviation from the consensus shown. Primers are shown in boldface. Exon boundaries indicated with small vertical arrows. This sequence corresponds to the murine SAA1 gene (20) .

These data show that the murine SAA1 gene is constitutively transcribed in brains of normal BALB/cJ mice. Although this observation was unexpected (because the SAA proteins have been described as synthesized largely in liver but also in spleen and leukocytes), the lipophilicity of SAA proteins (10 , 11) at least suggested that they might have legitimate roles in brain physiology.

Murine brain SAA1 transcription pattern after virus infection
Figure 3 shows levels of SAA1 expression compared with the patterns of IL-6, TNF-{alpha}, and IL-lß before and at intervals after Sindbis virus infection. Several features are apparent:



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  		Figure 3. Relative brain mRNA levels for SAA, TNF-{alpha}, IL-1ß, and IL-6 determined by RT-PCR at different times (in days) after infection with AR339. Expressed as percent of maximum level for each transcript type.

1) SAA mRNA levels fall immediately after infection and remain low for up to 6 wk. Control mice inoculated with HBSS showed a similar decrease in SAA mRNA levels, suggesting that inoculation trauma or HBSS itself may affect SAA expression;

2) IL-6 and TNF-{alpha} mRNA levels reach peaks at 6 h and 7 days postinfection, respectively. Finding low levels on day 4 is consistent with the earlier report by Wesselingh et al. (19) , who found the highest inter-animal variations on days 3–4; they attributed these variations to differences in rates of mononuclear cell influx into the brain. Thus, the trends to a consistent rise in TNF-{alpha} mRNA levels to day 7 and a consistent fall in IL-6 mRNA levels from the outset are more likely the case and similar to those found in the earlier study where measurements were not reported for day 4 (19) . IL-1ß mRNA levels rise later, with a peak around day 9;

3) Brain SAA mRNA levels do not rise in response to an increased expression of mRNAs for TNF-{alpha}, IL-6, and IL-1ß (which presumably reflects the synthesis of the respective proteins) of nearly two orders of magnitude.

Our finding low levels of brain SAA mRNA in the presence of an increase of nearly two orders of magnitude in TNF-{alpha} and IL-6 mRNA levels is a striking contrast to the effects of these same cytokines on hepatocytes, where they induce a large increase in SAA mRNA expression in the first 18–24 h after exposure (4 5 6 7 8 , 21) . In our mice, liver SAA mRNA levels rose modestly only 1–2 wk after brain infection (see Fig. 4 ). This rise was seen at the same time as modest doubling of the liver TNF-{alpha} mRNA level and is compatible with liver infection by newly replicated AR339. The relatively low level of stimulation of liver TNF-{alpha} mRNA expression presumably reflects the low titer of AR339 released from the infected brain and its low efficiency for liver infection. Liver IL-6 mRNA was not induced (data not shown).



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  		Figure 4. Relative hepatic mRNA levels for SAA and TNF-{alpha} determined by RT-PCR at different times (in days) after brain infection with AR339. Note that the changes are later and smaller than those shown in Fig. 3 . The changes in mRNA levels in control mice were not statistically significant. Expressed as percent of maximum level for each transcript type.

This remarkable contrast between SAA mRNA response patterns in brain and liver is compatible with several possibilities:

1) TNF-{alpha} and IL-6 in brain do not reach the cells responsible for SAA mRNA expression;

2) Signal transduction pathways responding to TNF-{alpha} and IL-6 in brain differ from those in liver. This is consistent with our observation that levels of brain SAA mRNA begin to fall early after infection, even before the peaks of TNF-{alpha} and IL-6 mRNA;

3) The trauma of intracerebral inoculation may reduce SAA mRNA transcription in brain without affecting the cytokine responses;

4) Neurons may be the site of constitutive brain SAA mRNA expression in mice. In human brains, in situ hybridization has shown SAA mRNA expression in cortical pyramidal neurons and cerebellar Purkinje cells (22) . Because neurons are primary targets of Sindbis virus infection (23) and Sindbis virus shuts off host cell protein synthesis early in infection, synthesis of SAA mRNA itself or some mediator of SAA mRNA expression may be reduced. (TNF-{alpha} and IL-6 are synthesized in other cell types.) However, this does not explain the decreased SAA mRNA levels after inoculation of HBSS alone.

As shown in Fig. 3 , there is no apparent delay or interruption of transcription of cytokines IL-1ß, IL-6, and TNF-{alpha} in response to AR339 infection; levels of these are similar to those reported before (18 , 19) . Thus, the persistent low levels of SAA mRNA after 8 days (when the virus infection has been cleared; 18 , 19 , 23 ) are unexpected, and we consider at least two explanations. 1) The neurons responsible for synthesizing SAA mRNA or its mediators may have been killed or damaged by the infection. However, mice recover from AR339 infection uneventfully, making it unlikely that enough neurons would be lost to inhibit SAA mRNA transcription to this extent unless a certain population of neurons, susceptible to AR339 infection, is also responsible for SAA mRNA transcription. 2) There may have been long-term postinoculation change(s) in molecule(s) responsible for inducing SAA mRNA expression.

If the second explanation is correct, however, this response pattern appears limited to the brain because there is a modest but significant increase in SAA (and TNF-{alpha}) mRNA induced in the liver at late times after brain infection (see Fig. 4 ).

Hardardóttir et al. did not detect SAA mRNA in brains of unstimulated Syrian hamsters, although it did appear after intraperitoneal (i.p.) injection of LPS. i.p. injection of TNF-{alpha} and IL-1ß did not lead to SAA mRNA production in these brains (24) . SAA was not detected by immunohistochemistry in the brains of normal rhesus monkeys (25) . In contrast to the findings in Syrian hamsters and monkeys, our data show that SAA mRNA transcription is constitutive in mouse brain. Low levels were detected by immunohistochemistry in normal human brains (26) .

SAA gene expression has been studied in liver or hepatocyte-derived systems (4 , 6 7 8 , 20) . Mice have low constitutive levels of hepatic SAA mRNA that rise rapidly after acute-phase stimuli (4 , 8 , 27) . SAA genes differ in 5' control elements. For example, murine SAA1 and SAA2 have NF-{kappa}B sites (7 , 28) whereas human SAA4 lacks an NF-{kappa}B site, but has a prominent AP-1 site (29) . Additional 5' sequence information has been identified for SAA genes in humans and mice, but these regions have not been characterized fully. TNF-{alpha} activates NF-{kappa}B but, as our data show, SAA mRNA transcription in the mouse brain is not stimulated by local synthesis of TNF-{alpha}.

Our observations are significant in relation to both normal brain function and central nervous system responses to infection and inflammation. For example, the pathological changes of Alzheimer’s disease involve inflammatory cells and proteins. Activated microglia/macrophages with MHC class II antigens are conspicuous (30 31 32 33) . Senile plaques contain cytokines (IL-1, IL-6, TGF, TNF-{alpha}), complement factors, pentraxins, and other inflammatory proteins. Local astrocytes, microglia, and neurons of Alzheimer’s disease brains contain mRNAs for most of these proteins, supporting the notion that these cytokines arise endogenously (34 35 36 37) . A causal relationship between the chronic activation of brain glia that occurs in aging and the deposition of inflammatory proteins and ß-amyloid in brain plaques has been proposed (38) . Thus, although these cytokines (known inducers of hepatic acute-phase protein synthesis) are present, our data indicate that they do not induce SAA mRNA expression in mouse brain after Sindbis virus (AR339) infection.

Liang et al. found SAA1 proteins in extracts of brains from humans with Alzheimer’s disease as well as low levels of SAA mRNA, but the stimulus(i) for SAA gene expression was(were) not identified (39) . Subsequently, immunohistochemistry of brains from individuals with Alzheimer’s disease showed SAA deposition in myelin sheaths and axonal membranes but not in plaques and tangles (26) . Similar changes were found in brains from individuals with multiple sclerosis (26) . Immunohistochemistry also localized SAA to capillaries and microinfarcts of hypertensive (but not normotensive) rhesus monkeys (25) . Thus, vascular damage or primary inflammation of myelin (as in multiple sclerosis) can be associated with localized SAA accumulation in the brain. These pathological associations are consistent with the known interactions of SAA with lipids (10 , 11) and cholesterol (15 , 40) .

T cell-dependent factors are unlikely to explain the early fall in SAA mRNA expression that we have observed, because the T cell response to Sindbis virus infection develops only ~3 days after infection. By contrast, synthesis of IL-1, IL-4, IL-6, IL-lß, TNF-{alpha}, and TGF-ß in cells intrinsic to the brain begins immediately after infection (23 , 41 , 42) ; our data have reproduced several of these patterns.

It will be important to determine the site(s) of SAA mRNA synthesis in the mouse brain, particularly to distinguish between neuronal and non-neuronal cells. Using immunohistochemistry and in situ hybridization in normal human tissues, Urieli-Shoval et al. showed that pyramidal cells in the cortex and Purkinje cells in the cerebellum express SAA mRNA and protein (22) . Circulating blood leukocytes are unlikely to be responsible for the brain SAA mRNA expression we have observed. Relatively few leukocytes are present in our specimens; if present, they would be expected to show stimulated SAA mRNA expression in response to the cytokines. It also will be important to determine the concentration of SAA proteins present.

The basis for the striking lipophilicity of native SAA proteins is unknown (10 , 11 , 15 , 40) . Primary sequences of SAA proteins include ~40% charged residues, and so the lipophilicity must at least reflect folding. Clearly, the amino-terminal residues of SAA proteins are lipophilic (1 , 2 , 15) , but our unpublished observations have shown that removing the 6 amino-terminal residues does not increase solubility and leads to denaturation. Unfortunately, because of their intrinsic insolubility SAA proteins have resisted many structural studies. Our study of an SAA fusion protein has shown that both helical and ß-sheet domains are present (43) . Further characterization of the structure of folded SAA should help explain the function and distribution of SAA in the normal brain as well as in response to infection, inflammation, aging, and other degenerative processes.


   ACKNOWLEDGMENTS
 
We thank Dr. Diane Griffin for helpful advice and encouragement. Technical assistance was provided by Steve Choi and Yaqing Shi. Mrs. Mary A. Mix provided secretarial support. This work was performed under USPHS grants AI01070–02 and NS29234 and assisted by generous gifts from Mr. and Mrs. William M. Griffin, Mr. Daniel M. Kelly, and in memory of Alexander MacWatt.


   FOOTNOTES
 
1 Deceased.

Received for publication April 4, 2001. Revision received June 19, 2001.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 

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I. Mori, F. Goshima, T. Koshizuka, N. Koide, T. Sugiyama, T. Yoshida, T. Yokochi, Y. Nishiyama, and Y. Kimura
Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus
J. Gen. Virol., September 1, 2003; 84(9): 2401 - 2408.
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