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The Journal of Immunology, 1998, 160: 2570-2572.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: The Induction of Acute Phase Proteins by Lipopolysaccharide Uses a Novel Pathway That Is CD14-Independent1

Alain Haziot, Xing Y. Lin, Fan Zhang and Sanna M. Goyert2

Division of Molecular Medicine, North Shore University Hospital, NYU School of Medicine, Manhasset, NY 11030


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
LPS (endotoxin) and proinflammatory cytokines (IL-6, IL-1, and TNF-{alpha}) are potent inducers of acute phase proteins (APP). Since LPS induces high levels of these cytokines after its interaction with CD14, a protein expressed on the surface of monocytes and neutrophils, it has been assumed that CD14 mediates the LPS induction of APP expression. To test this hypothesis, CD14-deficient and control mice were injected with low doses of LPS, and the expression of several APP that are normally up-regulated by LPS was measured. CD14-deficient mice showed no alteration in the induction of APP, including serum amyloid A, LPS-binding protein, fibrinogen, or ceruloplasmin; in contrast, C3H/HeJ mice, which carry a mutation in the Lps gene, do not up-regulate the expression of these proteins. These studies show that the up-regulation of APP by LPS utilizes a non-CD14 receptor and requires a functional Lps gene.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Among the many effects of LPS, a major constituent of the outer membrane of Gram-negative bacteria, is its ability to induce the expression of acute phase proteins (APP).3 APP are a set of functionally diverse proteins thought to increase host defenses as well as promote a return to a normal condition by controlling inflammation (1, 2). It has been widely assumed that the APP response to LPS involves CD14, the major receptor for LPS expressed on the surface of monocytes and neutrophils (3, 4, 5), since the interaction of LPS with CD14 results in the induction of cytokines (IL-6, IL-1, and TNF-{alpha}) that are known to stimulate APP expression by the liver (6). We have previously shown that CD14-deficient mice do not produce significant levels of these cytokines even when exposed to high levels of LPS (20 mg/kg body weight) (7). To address the role of CD14 in the induction of the APP response, the ability of CD14-deficient mice to produce several representative APP in response to low doses of LPS was investigated. Surprisingly, no defect in APP induction was observed.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

CD14-deficient mice (7), 6 to 12 weeks old, back-crossed one or five times to C57BL6/J mice, and control C57BL6/J mice (The Jackson Laboratory, Bar Harbor, ME), age and sex matched, were used. Ten-week-old C3H/HeJ and C3H/HeN mice were obtained from The Jackson Laboratory and Harlan Sprague Dawley (Madison, WI), respectively. Animals were housed in a conventional facility.

Induction of acute phase responses

Mice were injected i.p. with 0.2 ml of a solution of either LPS from Salmonella minnesota wild type (Sigma Chemical Co., St. Louis, MO), LPS from Escherichia coli K235 (a gift of Dr. S. Vogel, Department of Immunology and Microbiology, Uniformed Services University of the Health Sciences, Bethesda, MD), synthetic lipid A (Salmonella, biphosphate (ICN Pharmaceuticals, Costa Mesa, CA)) in nonpyrogenic saline (Baxter Healthcare Corp., Deerfield, IL) or nonpyrogenic saline alone. As a positive control for production of APP, mice were injected s.c. with a 3% w/v solution (0.15 ml/mouse) of silver nitrate (Mallinckrodt Chemical, Paris, KY) in nonpyrogenic water (Baxter Healthcare Corp.). After 24 or 36 h as indicated, blood was collected by heart puncture using heparin or EDTA as an anticoagulant as described in the text.

Determination of serum amyloid A (SAA) concentration in the plasma

Plasma was collected from heparinized blood, and the concentration of SAA was measured by ELISA (Biosource International, Camarillo, CA).

Determination of fibrinogen concentration in the plasma

Plasma was collected from citrated blood and the concentration of fibrinogen was determined by ammonium sulfate precipitation and turbidity measurement (8). Briefly, 0.04 ml of plasma was mixed with 1 ml of reagent solution (ammonium sulfate (1.085 M), sodium chloride (0.115 M), potassium phosphate dibasic (12.4 mM), pH 6.8). After a 20-min incubation at room temperature, the turbidity was determined at 622 nm. A standard curve established in each assay with a fibrinogen reference plasma (Sigma Chemical Co.) was used to determine the concentrations of the samples. The range of linearity of the standard curve was 0.29 to 2.35 mg/ml.

Determination of ceruloplasmin concentration in plasma

The oxidase activity of ceruloplasmin was measured as described (9). Briefly, a mixture of 0.015 ml of serum and 0.385 ml of 0.1 M acetate buffer (pH 5) was prepared in duplicate and warmed to 30°C in a water bath. After addition of 8 mM o-dianisidine (0.1 ml, Sigma Chemical Co.), one set of samples was incubated for 5 min (to serve as blanks) and the other set was incubated for 15 min (sample tubes). The reaction was stopped with the addition of 1 ml of sulfuric acid (9 M). The OD540 nm of each sample was read against its blank. Human ceruloplasmin (Sigma Chemical Co.) was used as a standard from which the concentration of the samples was computed.

Cytokine analyses

The concentration of TNF-{alpha} in serum was measured by a bioassay using Wehi 2F cells as described (5); the lower limit of detection for this assay is 0.72 pg/ml. The concentration of IL-6 in serum was measured by ELISA (Endogen, Woburn, MA). Animals were injected with LPS (100 µg/kg) and bled at various times (30, 60, 90, 120, 180, 240 min) for cytokine analysis.

RNA isolation and Northern blot analysis

Liver fragments were collected 24 h after injection and frozen immediately in liquid N2. Frozen liver fragments were crushed in a mortar, and RNA was isolated using Tri-Reagent (Molecular Research Center, Cincinnati, OH) and subjected to Northern blot analysis (10). Membranes were probed with 32P-labeled cDNA fragments of SAA1 (ATCC 59504, digested with PstI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (ATCC 57090, digested with PstI-XbaI), and rat LPS-binding protein (LBP, digested with EcoRI (11)), a gift from Dr. T. Billiar, Department of Surgery, University of Pittsburgh, Pittsburgh, PA. Quantitative analysis was done using a PhosphorImager SF and ImageQuant software (Molecular Dynamics, Sunnyvale, CA). The intensity of each band was quantitated and normalized to the GAPDH content of the sample.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Mice (CD14-deficient and control) were injected with LPS (2 mg/kg body weight), and the degree of induction of several representative type 1 and type 2 APP was determined. The primary organ for production of APP is the liver, where their production is transcriptionally regulated (12). Type 1 APP are primarily regulated by IL-1 and TNF-{alpha} and include SAA, LBP (13, 14), {alpha}1-acid glycoprotein, complement C3, and C-reactive protein, whereas type 2 APP are regulated by IL-6 and include fibrinogen, {alpha}1-antitrypsin, and ceruloplasmin (reviewed in Reference 1). As seen in Figure 1Go, CD14-deficient and control C57BL6/J mice injected with S. minnesota, wild-type LPS produce similar levels (~400 µg/ml) of SAA, whereas mice injected with saline produce negligible amounts of SAA (<70 µg/ml), similar to the level detected in noninjected mice in our facility. No differences in the APP response to LPS were observed between mice backcrossed once or five times to C57BL6/J, indicating that genetic differences contributed by the 129/Sv embryonic stem cells used to generate the original CD14-deficient mice do not influence the APP response. To exclude the possibility that the LPS response in CD14-deficient mice is caused by contaminating bacterial protein present in the commercial LPS preparation, SAA induction was determined after injection with protein-free LPS isolated from E. coli K235 or with synthetic lipid A (2 mg/kg). In both cases, the induction of SAA was similar in CD14-deficient and control mice and comparable with that observed with commercially available LPS (Fig. 1Go). Analyses of LPS-induced SAA production by CD14-deficient mice backcrossed five times with a different strain (BALB/c) showed that BALB/c-CD14-deficient mice produce levels of SAA similar to those in C57BL6/J-CD14-deficient mice, indicating that the ability of CD14-deficient mice to produce APP in response to LPS is not dependent on the C57BL6/J genetic background (L. Khemlani and S. M. Goyert, unpublished results).



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  		FIGURE 1. SAA production by mice injected with LPS and lipid A. CD14-deficient (first backcross to C57BL6/J) and control mice were injected i.p. with 2 mg/kg body weight of LPS from S. minnesota wild-type (n = 4), protein-free LPS from E. coli K235 (n = 2), synthetic lipid A (n = 2), or nonpyrogenic saline (n = 2). Twenty-four hours later, blood was collected, and the concentration of SAA in the heparinized plasma was determined by ELISA. Results are presented as mean ± SE.

 
The increase in serum levels of SAA is accompanied, in both CD14-deficient and control mice, by increases in the levels of SAA mRNA transcribed in the liver (Fig. 2Go). Similarly, comparable increases in the RNA levels of another type I APP, LBP, were observed in both CD14-deficient and control mice (data not shown).



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  		FIGURE 2. Northern blot analysis of the expression of SAA in the liver. Total RNA from livers of CD14-deficient mice and control mice injected 24 h earlier with 2 mg/kg body weight LPS from S. minnesota, wild type (i.p.), a 3% solution of silver nitrate (0.15 ml s.c.) (nonspecific control for the production of APP), or nonpyrogenic saline was probed with 32P-labeled cDNA fragments from SAA1 and GAPDH. Quantitative analysis was performed using a PhosphorImager. Results (mean of three independent experiments) are presented as the intensity of the band normalized to GAPDH content and by arbitrarily defining as 100 the response to silver nitrate in each experiment.

 
To measure type II APP responses, the serum concentration of fibrinogen was measured after injection of LPS (2 mg/kg). As shown in Figure 3Go, analogous to what was found with SAA, comparable levels of fibrinogen were detected in CD14-deficient and control mice after injection of LPS. Similarly, the serum concentration of ceruloplasmin, another type II APP, increased comparably over basal levels in CD14-deficient (3.6-fold) and control (2.3-fold) mice after injection of LPS.



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  		FIGURE 3. Plasma concentration of fibrinogen in mice injected with LPS. CD14-deficient mice (fifth backcross to C57BL6/J) and C57BL6/J mice were injected i.p. with 2 mg/kg body weight of protein-free LPS from E. coli K235. Thirty-six hours later, blood was collected, and the concentration of fibrinogen in the citrated plasma was determined by ammonium sulfate precipitation and turbidimetry measurement. Results are presented as mean ± SE (n = 2); differences between CD14-deficient and control animals treated with LPS are not statistically significant.

 
To determine whether the dose of LPS required for induction of APP expression is the same in CD14-deficient as in control mice, a dose response analysis was performed. As seen in Figure 4Go, a similar amount of LPS (50 µg of LPS per kg of body weight or a total of 1 µg of LPS for an average 20-g mouse) was required to induce an SAA response in both CD14-deficient and control mice and the levels of SAA at different doses of LPS were comparable for CD14-deficient and control mice. In summary, we have analyzed LPS induction of APP in 28 control mice and 34 CD14-deficient mice and find no significant differences in expression, indicating that CD14 does not play a role in this response to LPS.



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  		FIGURE 4. Analysis of the SAA production induced by increasing doses of LPS. CD14-deficient mice (fifth backcross to C57BL6/J) and C57BL6/J mice were injected i.p. with increasing doses of LPS from S. minnesota, wild type. Twenty-four hours later, blood was collected, and the concentration of SAA in the heparinized plasma was determined by ELISA. Results are presented as mean ± SE (n = 2).

 
These observations are strikingly different from those previously observed for C3H/HeJ mice that are hyporesponsive to LPS. The defect in these mice is due to a spontaneous mutation mapping to a locus (Lps) located on chromosome 4 (15). In addition to being hyporesponsive to LPS, C3H/HeJ mice make no APP response when exposed to LPS (16), an observation that we have confirmed. In our experiment, injection of LPS (2 mg/kg) into C3H/HeJ and control, LPS-responsive C3H/HeN mice resulted in no increase in SAA in the serum of C3H/HeJ mice (basal level, 12.2 ± 5 µg/ml) in contrast to a dramatic increase of SAA to 554.5 ± 45 µg/ml in the serum of C3H/HeN mice. It had been assumed that the inability of C3H/HeJ mice to make APP in response to LPS is caused by their inability to make significant levels of proinflammatory cytokines (IL-6, IL-1ß, TNF-{alpha}) in response to LPS. In our previous studies, injection of a high dose of LPS ({approx}400 µg/mouse) resulted in very little if any circulating cytokine production in CD14-deficient mice (7), and yet they produce normal levels of APP. Furthermore, injection of CD14-deficient mice with a low dose of LPS used to elicit APP in this study (100 µg/kg or {approx}2 µg/mouse) results in no detectable circulating TNF-{alpha} and a very low level of circulating IL-6 (7.6 ± 2.5 ng/ml or 1/15 the amount produced by normal mice). These observations indicate that there is a non-CD14 pathway for the induction of APP by LPS and suggest that this pathway does not require the induction of circulating cytokines. This is consistent with previous observations that the induction of APP by LPS, in contrast to other inducers of APP, is TNF-{alpha}, IL-1, and IL-6 independent (17, 18). In summary, our studies indicate that although CD14 does not play a role in LPS-induced APP expression, the Lps gene is a key component in this novel pathway.


   Acknowledgments
 
We thank Dr. Jack Silver for a critical reading of the manuscript.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant AI23859 and The Council for Tobacco Research Grant 2218 (S.M.G.) and the American Heart Association New York State Affiliate Grant-In-Aid 960159 (A.H.). This is manuscript no. 68 from the Division of Molecular Medicine, Department of Medicine, North Shore University Hospital/NYU School of Medicine. Back

2 Address correspondence and reprint requests to Dr. Sanna M. Goyert, Division of Molecular Medicine, North Shore University Hospital, NYU School of Medicine, 350 Community Drive, Manhasset, NY 11030. E-mail address: Back

3 Abbreviations used in this paper: APP, acute phase proteins; SAA, serum amyloid A; LBP, lipopolysaccharide-binding protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Back

Received for publication December 9, 1997. Accepted for publication January 20, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Mackiewicz, A., I. Kushner, H. Baumann. 1993. Acute Phase Proteins: Molecular Biology, Biochemistry, and Clinical Applications 686 pp. CRC Press, Boca Raton, FL.
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  4. Wright, S. D., R. Ramos, A. Hermanowski-Vosatka, P. Rockwell, P. A. Detmers. 1991. Activation of the adhesive capacity of CR3 on neutrophils by endotoxin: dependence on lipopolysaccharide binding protein and CD14. J. Exp. Med. 173:1281.[Abstract/Free Full Text]
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  6. Baumann, H., J. Gauldie. 1990. Regulation of hepatic acute-phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol. Biol. Med. 7:147.[Medline]
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  8. Stakenburg, J., H. Neumann. 1977. A rapid and simple fibrinogen determination. Clin. Chim. Acta 80:141.[Medline]
  9. Schosinsky, K. H., H. P. Lehman, M. F. Beeler. 1974. Measurement of ceruloplasmin from its oxidase activity in serum by use of o-dianisidine hydrochloride. Clin. Chem. 20:1556.[Abstract]
  10. Ferrero, E., C.-L. Hsieh, U. Francke, S. M. Goyert. 1990. CD14 is a member of the family of leucine-rich proteins and is encoded by a gene syntenic with multiple receptor genes. J. Immunol. 145:331.[Abstract]
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