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The Journal of Immunology, 1999, 162: 3596-3600.
Copyright © 1999 by The American Association of Immunologists

Paradoxical Preservation of a Lipopolysaccharide Response in C3H/HeJ Macrophages: Induction of Matrix Metalloproteinase-91

Fen-yu Jin2, Carl F. Nathan and Aihao Ding3

Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, NY 10021


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
C3H/HeJ mice carry a mutant allele (Lpsd) of a recently identified gene whose normal allele (Lpsn) confers responsiveness to bacterial LPS in C3H/HeN and most other mouse strains. Recently we reported a differential display analysis of matched macrophage-derived cell lines from C3H/HeJ and C3H/HeN mice under LPS-free conditions. Of the ~12,000 transcripts evaluated, 4 were differentially expressed. One transcript represented secretory leukocyte protease inhibitor. In this study, we report another differentially expressed transcript, mouse matrix metalloprotease-9 (MMP-9). Like secretory leukocyte protease inhibitor, MMP-9 was expressed constitutively in the Lpsd macrophage cell line and not in the Lpsn cell line. Similarly, two additional macrophage cell lines that respond readily to LPS by producing nitric oxide and TNF expressed no MMP-9 under LPS-free conditions. However, in all four cell lines, LPS induced MMP-9 or augmented its expression. In primary macrophages, concentrations of LPS in the ng/ml range augmented the expression of MMP-9 mRNA. Paradoxically, macrophages from Lpsd mice expressed more MMP-9 transcripts than macrophages from Lpsn mice. In contrast, the induction of TNF in response to LPS was much more pronounced in Lpsn macrophages. The present findings with MMP-9 suggest that homozygosity at Lpsd does not so much prevent a response to LPS as dysregulate it, resulting in the suppression of some LPS signaling pathways and the preservation of others.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cells that provide innate immunity are geared to respond promptly and emphatically to trace amounts of endotoxic bacterial LPS. Despite an extensive catalog of molecules involved in LPS recognition, signal transduction, and induced transcription 1, 2, 3, 4, 5 , an integrated view of the genetic and biochemical regulation of LPS responsiveness is lacking. The most intensively studied example of genetic regulation of LPS responses involves a mutation in a locus (Lps) on chromosome 4 in the C3H/HeJ mouse, as a result of which these mice and their macrophages, B cells, T cells, and fibroblasts are LPS hyporesponsive compared with the ostensibly congenic strain, C3H/HeN (Lpsn) 6, 7, 8, 9, 10, 11 . Recently, we used differential display analysis 12 to compare the mRNA profiles of matched macrophage cell lines derived from C3H/HeN (Lpsn) and C3H/HeJ (Lpsd) mice, respectively. Cultured cells were used to avoid natural exposure to LPS, so that differential expression of transcripts might cause, but could not be caused by, differential LPS responsiveness.

One cDNA identified by that analysis proved to be an LPS-inducible LPS response inhibitor, novel characteristics of a previously identified protein, secretory leukocyte protease inhibitor (SLPI)4, 13 . Only 3 other differentially expressed transcripts were detected among the ~12,000 compared. One differentially expressed transcript encoded matrix metalloproteinase-9 (MMP-9) (gelatinase), whereas the remaining two corresponded to previously unidentified genes 14 . Characterization of MMP-9 expression is reported in this study. LPS hyporesponsive C3H/HeJ (Lpsd) primary macrophages responded to LPS by increasing MMP-9 expression better than C3H/HeN (Lpsn) primary macrophages. This paradoxical LPS-normoresponsive phenotype in otherwise LPS-hyporesponsive cells suggests that LPS responses must proceed down distinct pathways that are regulated in different fashions by the Lps gene product.


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

Charles River Breeding Laboratories (Wilmington, MA) and the Jackson Laboratories (Bar Harbor, ME) supplied C3H/HeN (Lpsn) and C3H/HeJ (Lpsd) female mice, respectively.

Cells

ANA-1 cells were kindly provided by Dr. L. Varesio (National Cancer Institute, Frederick, MD), and HeNC2 (from C3H/HeN (Lpsn) mice) and GG2EE cells (from C3H/HeJ (Lpsd) mice) were provided by Dr. D. Radzioch (McGill University, Montreal, Canada). All are bone marrow-derived macrophage lines 15, 16 . The RAW 264.7 mouse macrophage cell line was from American Type Culture Collection (Manassas, VA). Primary macrophages were collected from the peritoneal cavity 4 days after i.p. injection of 2 ml of 4% Brewer’s thioglycollate broth (Difco, Detroit, MI). Cells were maintained in RPMI 1640 supplemented with 10% heat-inactivated FBS (HyClone, Logan, UT), 2 mM L-glutamine, 200 U/ml penicillin, and 200 µg/ml streptomycin at 37°C in 5% CO2/95% air. Complete culture medium was routinely monitored for LPS contamination by the chromogenic Limulus amebocyte lysate assay (BioWhittaker, Walkersville, MD) and found to contain <25 pg LPS/ml.

Differential display of mRNA

DNA-free total RNA from HeNC2 and GG2EE cells was used for differential display with a random 10-mer and T12M(C, G, T, A), in which M signifies a mixture of A, C, and G, as detailed elsewhere 13 . Differentially expressed products in the sequencing gel were extracted with H2O and reamplified twice by PCR using the same set of primers under the same conditions. The reamplified PCR product was gel purified using a Gel Extraction kit (Qiagen, Chatsworth, CA), subcloned into the PCR TA cloning vector (Invitrogen, San Diego, CA) and sequenced.

Northern blot analysis

Total RNA (20 or 25 µg/lane) from primary macrophages or cell lines was electrophoresed on a 1% agarose gel with 0.2 M 3[N-morpholino] propanesulfonic acid (pH 7.0), 0.5 M sodium acetate, 10 mM EDTA (1x MOPS), and 2% formaldehyde, confirming equal loading by means of staining with 2.5 µg/ml ethidium bromide. RNA was transferred in 20x SSC onto nylon membranes (NEN Research Products, Boston, MA). Membranes were hybridized for 18 h at 42°C with probe labeled (106 cpm/ml) with Priming-A-Gene kit from Promega (Madison, WI) in 5x SSC, 5x Denhart buffer, 50% formamide, plus 1% SDS and washed extensively before autoradiography. Control probes consisting of ß-actin or glyceraldehyde-3-phosphate dehydrogenase (G3PDH) cDNAs were amplified with ß-actin or G3PDH amplimers (Clontech Laboratories, Palo Alto, CA) from templates provided with the amplimers.

dsDNA sequencing

Subcloned DNA was sequenced by the dideoxynucleotide chain termination method using Sequence Version 2.0 DNA sequencing kit (United States Biochemical, Cleveland, OH) according to the manufacturer’s instructions.

Additional materials

LPS prepared from Escherichia coli 0111:B4 by phenol extraction was from List Biological Laboratories (Campbell, CA) and contained <0.8% protein; this LPS was used unless indicated otherwise. LPS prepared from E. coli K235 by phenol-water extraction was kindly provided by Dr. Stefanie Vogel (Uniformed University, Bethesda, MD) with <0.008% protein. Other reagents were mouse rIFN-{gamma} (1.1 mg protein/ml; sp. act. 5.2 x 106 U/mg; LPS content <10 pg/ml) from Genentech (South San Francisco, CA); oligonucleotide primers from Oligos Etc. (Guilford, CT); reverse transcription buffer and Moloney murine leukemia virus reverse transcriptase from Life Technologies (Grand Island, NY); restriction enzymes from New England Biolabs (Beverly, MA); AmpliTaq DNA polymerase, dNTPs, and PCR buffer solutions from Perkin-Elmer Cetus (Foster City, CA); guanidinium isothiocyanate, formaldehyde, and formamide from Fluka Chemica-Biochemica (Ronkonkoma, NY); and all other reagents from Sigma (St. Louis, MO). Plasmid DNA preparation columns were from Qiagen, and tissue culture dishes were from Corning Glass Works (Corning, NY).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Identification of MMP-9 as a transcript expressed differentially in a macrophage cell line carrying the Lpsd allele

The identically derived HeNC2 (Lpsn) and GG2EE (Lpsd) macrophage cell lines maintain the LPS-responsive (HeNC2) or LPS-hyporesponsive (GG2EE) phenotypes of their strains of origin as judged by LPS-induced nitric oxide and TNF-{alpha} production 13 as well as the resultant cytotoxicity toward tumor cells 16 . Differential display analysis of these two cell lines began with reverse transcription of their mRNA with oligodeoxythymidylate primers T12M(G, C, T, or A), in which M connotes a mixture of A, C, and G. Specific cDNA fragments were amplified by PCR with the same poly(dT) primer and 1 of 20 arbitrary 10-mers, whose binding positions in different transcripts were expected to vary in distance from the poly(A) tail, producing a ladder when amplified DNA was resolved on a polyacrylamide gel. From >12,000 resolved amplificands, 4 met the following criteria: in replicate experiments, they were consistently detectable from only one cell line, and they proved on subsequent analysis to represent distinct genes. One of these, SLPI, was the subject of a previous report 13 .

The cDNA fragments designated clones 3 and 23 were amplified by T12MA and GTTGGACCTA only from GG2EE (Lpsd) and not from HeNC2 (Lpsn) cells (Fig. 1GoA). These two fragments were excised from the polyacrylamide gel, reamplified, purified from agarose gels, and used as probes in Northern blot analyses. Clone 3 hybridized to mRNA from GG2EE cells (Lpsd), but not from HeNC2 (Lpsn) cells, whereas clone 23 identified two bands, one equally, and the other differentially expressed (Fig. 1GoB). This finding suggested that at the position in which fragment 23 had been excised, two different cDNA species had contributed amplificands of indistinguishable size. Accordingly, cDNA fragments 3 and 23 were both subcloned. Individual colonies of each were selected, whose DNA hybridized selectively and at the same Mr with mRNA from GG2EE cells (Lpsd) but not HeNC2 cells (Lpsn). These subclones were sequenced and found to be flanked by primer binding sites corresponding to those used in the original RT-PCR analysis and to be identical with each other. The subclones of clones 3 and 23 were completely concordant in sequence with mouse MMP-9 (gelatinase B; type IV basement membrane collagenase) (GenBank accession no. Z27231).



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  		FIGURE 1. Identification of a transcript displayed by GG2EE (G, Lpsd) cells but not HeNC2 (H, Lpsn) cells. A, Differential display of GG2EE (G) and HeNC2 (H) cells with T12MA and GTTGGACCTA (M stands for a mixture of A, C, and G.) The arrows indicate differentially displayed amplificands. B, Northern blot analysis. Reamplified DNA bands from A were purified and used in Northern blot analysis with 20 µg total RNA from HeNC2 (H, Lpsn) and GG2EE (G, Lpsd) cells to confirm their differential expression.

 
Constitutive and regulated expression of MMP-9 in four macrophage cell lines

We compared the basal levels of MMP-9 transcript in HeNC2, GG2EE, and two additional macrophage cell lines derived in a different manner from non-C3H backgrounds, RAW 264.7 and ANA-1. Only the GG2EE cells (Lpsd) expressed readily detectable MMP-9 mRNA under LPS-free conditions (Fig. 2Go). The three Lpsn lines were all negative for basal MMP-9 expression.



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  		FIGURE 2. Expression of MMP-9 in four macrophage cell lines and its regulation by LPS and IFN-{gamma}. Indicated cell lines were incubated with 100 ng/ml LPS and/or 10 U/ml IFN-{gamma} for 4 h, and RNA was prepared. Northern blot analysis was performed as in Fig. 1Go. with subclone 3 as a probe. RNA loading (20 µg/lane) was controlled with the ß-actin probe.

 
Because MMP-9, like SLPI 13 , was highly expressed in the LPS-hyporesponsive cell line, and because SLPI was LPS-inducible in primary macrophages 13 , we next asked whether MMP-9 may also be LPS-inducible. Moreover, because SLPI induction was inhibited by IFN-{gamma} 13 , a cytokine whose administration can correct or complement the LPS response defect in C3H/HeJ mice 17, 18, 19 , we tested the effects of IFN-{gamma}. In LPS-responsive cells (HeNC2, RAW 264.7, and ANA-1), MMP-9 mRNA was induced within 4 h of exposure to LPS (Fig. 2Go). This induction was completely inhibited by IFN-{gamma} (Fig. 2Go). The ability of LPS to induce MMP-9 in mouse macrophages extends previous reports in human 20 and rat 21 mononuclear phagocytes. Likewise, the ability of IFN-{gamma} to block LPS-induced expression of MMP-9 conforms to findings with rat microglia 21 .

Superinduction of MMP-9 by LPS in primary macrophages from C3H/HeJ mice

Primary peritoneal macrophages elicited from both C3H/HeN (Lpsn) and C3H/HeJ (Lpsd) mice by i.p. injection of thioglycollate broth expressed a low level of MMP-9 (Fig. 3Go). The difference in MMP-9 expression between these primary cells and bone marrow-derived cell lines may reflect differences in their origins, differentiation states, or past encounters. Expression of MMP-9 was augmented when these cells were exposed to 100 ng/ml of LPS in vitro, a concentration typically used in the study of LPS-inducible genes in C3H/HeN macrophages, such as TNF and inducible nitric oxide synthase 13, 22 . Surprisingly, up-regulation of MMP-9 was much more pronounced in macrophages from C3H/HeJ (Lpsd) mice than those from C3H/HeN (Lpsn) mice at both time points examined, 6 and 18 h (Fig. 3GoA). At 6 h, densitometric analysis indicated that 3.5 ± 0.4-fold (mean ± SEM, n = 5 experiments) greater levels of MMP-9 mRNA accumulated in primary macrophages from C3H/HeJ (Lpsd) mice compared with those from C3H/HeN (Lpsn) mice.



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  		FIGURE 3. Polymixin B inhibits induction of MMP-9 by LPS in primary macrophages. Thioglycollate-elicited peritoneal macrophages from C3H/HeN and C3H/HeJ mice were incubated with 100 ng/ml of LPS (List) for 6 h or as indicated in the presence or absence of 10 µg/ml polymixin B. Northern blot analysis was performed as in Fig. 1Go. The bar graph in A displays densitometric analysis in which the ratio of signal intensity for MMP-9 to that of ß-actin is defined as 1 for C3H/HeN cells not given LPS in vitro (first lane in Northern blot). The other ratios are displayed in proportion to this standard. The result was from one of five (A) or two (B) similar experiments.

 
The paradoxical result that the induction of MMP-9 was more pronounced in HeJ macrophages than in HeN macrophages raised a concern about the purity of the LPS used, because some LPS-associated proteins are capable of activating macrophages in an LPS-independent fashion 23 . To address this concern, we asked whether polymixin B, an LPS-binding antibiotic, could prevent MMP-9 induction by the LPS preparation used (List). As shown in Fig. 3GoB, addition of 10 µg/ml of polymixin B completely blocked the induction of MMP-9 from macrophages from either C3H/HeJ (Lpsd) or C3H/HeN (Lpsn) mice. This finding suggests that the entity in List’s LPS responsible for MMP-9 induction is LPS.

Differential regulation of MMP-9 and TNF in macrophages from C3H/HeN (Lpsn) and C3H/HeJ (Lpsd) mice

To check whether this phenomenon was relatively specific for MMP-9 induction, we next compared MMP-9 and TNF induction in response to LPS. For this experiment, a different preparation of LPS from E. coli K235 that contained <0.008% protein was used to reassure us that what we observed was not due to protein contamination in the commercial LPS preparation. Thioglycollate broth-elicited macrophages from C3H/HeJ (Lpsd) and C3H/HeN (Lpsn) mice were exposed to concentrations of this LPS ranging from 1 ng/ml to 10 µg/ml for 6 h, at which point the induction of MMP-9 and TNF transcripts was examined on the same membrane. As shown in Fig. 4Go, macrophages from C3H/HeJ mice were hyporesponsive to LPS in that they expressed little TNF mRNA, whereas macrophages from C3H/NeN mice expressed abundant TNF mRNA in response to LPS. However, induction of MMP-9 by LPS demonstrated an opposite pattern in these two cells: macrophages from C3H/NeJ mice expressed MMP-9 mRNA in response to LPS, whereas no MMP-9 mRNA was detectable in LPS-treated macrophages from C3H/HeN mice (Lpsn). This result rules out the possibility that the primary macrophages from C3H/HeJ (Lpsd) mice may have been activated in vivo 17, 24, 25 and points to differential LPS responsiveness in C3H/HeJ cells.



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  		FIGURE 4. LPS-induced expression of MMP-9 and TNF-{alpha} in primary macrophages from C3H/HeN and C3H/HeJ mice. Thioglycollate-elicited peritoneal macrophages from C3H/HeN and C3H/HeJ mice were treated with 0, 0.001, 0.01, 0.1, 1, or 10 µg/ml of LPS (gift of Dr. Stefanie Vogel) for 6 h. Northern blot analysis was performed as in Fig. 1Go with MMP-9 and TNF-{alpha} cDNA probes. Equal RNA loading was controlled with the ß-actin probe. This is one of three similar experiments.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The analysis of cDNAs representing transcripts differentially expressed by matched macrophage cell lines from Lpsn and Lpsd mice under LPS-free conditions has led to the isolation of two novel cDNAs 14 and the discovery of a previously unsuspected compound phenotype in the Lpsd mouse 13 . In this study, we report that the Lpsd allele was paradoxically associated with normoresponsiveness to LPS in the induction of another differentially expressed product, MMP-9. Previous studies have demonstrated that the LPS response defect in C3H/HeJ mice is not absolute. Even without intentional exposure to IFN-{gamma}, cells from these mice can respond partially, slowly, or weakly to LPS by several criteria, including activation of NF-{kappa}B 26 and expression of MnSOD 27 or SLPI 13 . However, the present report may be the first to identify an LPS response in C3H/HeJ cells that is more robust than that in C3H/HeN cells under the same conditions. This response is unlikely to be due to a protein impurity within the LPS preparation because the induction is polymixin B inhibitable and can be repeated with a relatively clean LPS preparation (Fig. 4Go). In addition, the same macrophages from C3H/HeJ mice responded poorly to the same LPS preparation by releasing TNF-{alpha} (Fig. 4Go). The implication of these findings is that the Lpsd allele seems to dysregulate the overall LPS response, not just suppress it.

There are other metalloproteinases within macrophages that can be regulated by LPS. Duc Dodon and Vogel 28 reported that LPS induced an inhibition in secretory elastase activity from thioglycollate-elicited macrophages. In contrast to the present report, this inhibition was only seen in LPS-responder macrophages and not in macrophages from C3H/HeJ mice.

It is of interest that LPS induces macrophages to release both a protease, MMP-9, and a protease inhibitor, SLPI. Zhang et al. 29 reported that SLPI interfered with the production of MMP-9 by human monocytes. However, such interference seems unlikely in the mouse macrophages studied here in which the expression of both SLPI and MMP-9 rose and fell in parallel, rather than reciprocally, upon exposure to LPS or IFN-{gamma}, respectively. Although SLPI functions as an LPS-induced LPS-response inhibitor 13 , the role of MMP-9 in the LPS response is unknown. A proinflammatory contribution is plausible, considering that MMPs promote cell migration in inflammation 30, 31, 32 , tissue remodeling 33 , and wound healing 34 , as well as tumor invasion 35, 36, 37 , and thus may permit macrophages to migrate toward sources of LPS and help destroy infected tissue. Alternatively, MMP-9, like SLPI, may inhibit LPS responses. This speculation is based on the LPS-induced expression of MMP-9 in C3H/HeJ cells, most of whose LPS responses are blunted. MMP-9 may degrade extracellular matrix proteins whose integrin-mediated signals serve as cofactors for macrophage activation by LPS 38, 39 .

The location of MMP-9 on mouse chromosome 2 (mouse genome, The Jackson Laboratory; http://mgd.hgmp.mrc.ac.uk) excludes its candidacy as the Lps gene on chromosome 4. Whether differential display analysis could yield an immediate candidate for the Lps gene remains unanswered. The inherent shortcomings of the method include that mutations in expressed genes need not lead to striking changes in the levels of their transcripts. Advantages of differential display include its sensitivity and its ability to detect disparities among any number of reference samples, disparities that reflect either silencing or overexpression of a given gene. The even-handedness of the method with respect to the populations under comparison was underscored by our identification of two transcripts (SLPI and MMP-9) that were overexpressed in LPS-hyporesponsive cells and an equal number that were overexpressed in LPS-normoresponsive cells. Microarray assays and/or sequential analysis of gene expression 40 are likely to overshadow differential display because of their greater speed of throughput but may suffer some of the same limitations.

Note added in proof. After this paper was accepted, the lps gene was identified as TLR4 41, 42 . Questions raised here and elsewhere about LPS signaling 43 remain.


   Acknowledgments
 
We thank Dr. Danuta Radzioch for providing HeNC2 and GG2EE cells and some of the primary macrophage mRNA, Dr. Luigi Varesio for ANA-1 cells, Dr. Stefanie Vogel for LPS, and Jenny Zhang for technical assistance.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants AI30165 (to A.D.) and GM53921 and AI34543 (to C.F.N.). Back

2 Current address: Millennium Pharmaceuticals, 640 Memorial Drive, Cambridge, MA 02139-4815. Back

3 Address correspondence and reprint requests to Dr. Aihao Ding, Box 57, Weill Medical College of Cornell University, New York, NY 10021. E-mail address: Back

4 Abbreviations used in this paper: SLPI, secretory leukocyte protease inhibitor; MMP-9, matrix metalloproteinase-9; G3PDH, glyceraldehyde-3-phosphate dehydrogenase. Back

Received for publication June 12, 1998. Accepted for publication December 7, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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