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The Journal of Immunology, 1999, 162: 1232-1235.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Coordinate Regulation of IFN Regulatory Factor-1 and the Polymeric Ig Receptor by Proinflammatory Cytokines1

Vincent J. Blanch*, Janet F. Piskurich{ddagger} and Charlotte S. Kaetzel2,*,{dagger}

Departments of * Microbiology/Immunology and {dagger} Pathology/Laboratory Medicine, University of Kentucky, Lexington, KY 40536; and {ddagger} Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The polymeric IgR (pIgR) mediates transcytosis of IgA across epithelial barriers of mucous membranes and exocrine glands. Synthesis of pIgR is up-regulated by the proinflammatory cytokines TNF-{alpha}, IFN-{gamma}, and IL-1 in HT-29 human colon carcinoma cells. We previously reported that IFN-{gamma} and TNF-{alpha} induce production of the transcription factor IFN regulatory factor-1 (IRF-1) in HT-29 cells and that IRF-1 binds to an element in exon 1 of the PIGR gene. We now report that levels of IRF-1 and pIgR mRNA are coordinately regulated in HT-29 cells by TNF-{alpha}, IFN-{gamma}, and IL-1ß. Furthermore, we demonstrate that in vivo expression of pIgR mRNA is greatly depressed in the intestine and liver of IRF-1-deficient mice. Our findings indicate a major role for the IRF-1 transcription factor in regulation of the PIGR gene and suggest a model for regulation of important genes in the mucosal immune system by proinflammatory cytokines.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Secretory IgA serves as the first line of specific immune defense, protecting the mucous membranes from inhaled, ingested, and sexually transmitted Ags (reviewed in 1 . The polymeric IgR (pIgR)3 mediates the transport of polymeric Ig, predominantly dimeric IgA, from the basolateral to the apical (lumenal) surface of mucosal epithelia and exocrine glands (reviewed in 2 . At the apical surface, pIgR is cleaved to a soluble fragment, also known as secretory component, and released into the lumen along with dimeric IgA to form secretory IgA. Since each molecule of pIgR can mediate only one round of cellular transport, a sustained increase in pIg transport requires an increased level of pIgR synthesis by the epithelial cell. The rate of pIgR synthesis is influenced by a number of cytokines and hormones that regulate the mucosal immune system (reviewed in 2 .

The HT-29 human colon carcinoma cell line has widely been used to model the regulation of pIgR expression by intestinal epithelial cells (Ref. 3, and references therein). Expression of pIgR by HT-29 cells is up-regulated by the proinflammatory cytokines IFN-{gamma} (4, 5, 6, 7), TNF-{alpha} (7, 8, 9), and IL-1 (10), as well as the Th2-type cytokine IL-4 (5, 7, 9). Studies in our laboratory of cytokines produced by in vitro-stimulated human intestinal lamina propria mononuclear cells suggested that the proinflammatory cytokine IFN-{gamma} was the central regulator of pIgR expression by intestinal epithelial cells (7). It has recently been reported that substantial proportions of human intraepithelial and lamina propria gut lymphocytes spontaneously secrete IFN-{gamma} and/or IL-4 (11).

At the molecular level, IFN-{gamma} has been shown to increase pIgR mRNA levels by a mechanism dependent on de novo protein synthesis (6, 12). We recently demonstrated that IFN-{gamma} and TNF-{alpha} cause de novo synthesis of the transcription factor IFN regulatory factor (IRF)-1 in HT-29 cells and that IRF-1 binds to a regulatory element in exon 1 of the human PIGR gene (13, 14). IRF-1 mRNA is known to be induced by proinflammatory cytokines, and this transcription factor has widely been implicated in the regulation of immune responses (reviewed in 15 . We now demonstrate that the levels of IRF-1 and pIgR mRNA are coordinately regulated by proinflammatory cytokines in HT-29 cells. We further show that pIgR mRNA levels are markedly reduced in tissues of IRF-1-deficient mice, suggesting an important role for IRF-1 in pIgR regulation in vivo.


   Materials and Methods
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 Abstract
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 Materials and Methods
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 References
 
Cell culture and cytokine treatments

The HT-29.74 subclone of the HT-29 human colon carcinoma cell line was originally selected for its ability to differentiate to an enterocytic phenotype in glucose-free medium (3). We isolated by limiting dilution a new subclone of HT-29.74 cells, HT-29v20, selected for high basal expression of pIgR and increased pIgR expression in the presence of IFN-{gamma}, TNF-{alpha}, or IL-1ß. HT-29v20 cells were plated in 60-mm dishes, at a concentration of 1.5 x 106 cells/dish, and induced to differentiate as described (3) by switching to glucose-free Leibovitz’s L-15 medium (Life Technologies, Gaithersburg, MD). Three days after switching to glucose-free medium, duplicate cultures of HT-29v20 cells were treated for 12 h (for analysis of IRF-1 mRNA) or 24 h (for analysis of pIgR mRNA) in the presence of varying combinations of cytokines. The concentrations of cytokines were 100 U/ml IFN-{gamma}, 10 ng/ml IL-1ß, and 10 ng/ml TNF-{alpha} (high dose) or 5 U/ml IFN-{gamma}, 0.5 ng/ml IL-1ß, and 0.5 ng/ml TNF-{alpha} (low dose) (R&D Systems, Minneapolis, MN).

Mice

Eight-wk-old male IRF-1-/- mice (16), backcrossed onto a B6 background, and wild-type age-matched male B6 mice were maintained in a specific pathogen-free environment until tissues were harvested.

RNA extraction and quantitative RT-PCR for pIgR and IRF-1 mRNA

Total cellular RNA was extracted from HT-29v20 cells and mouse tissues using TRIzol reagent according to the manufacturer’s protocol (Life Technologies). Levels of pIgR and IRF-1 mRNA from HT-29v20 cells and mouse tissues were determined by quantitative RT-PCR. Primer pairs for pIgR, IRF-1, and ß-actin are shown in Table IGo. Reactions were conducted using the Access RT-PCR kit according to the manufacturer’s protocol (Promega, Madison, WI). Reverse transcription was conducted at 48°C for 45 min, followed by inactivation of the enzyme at 94°C for 4 min. PCR conditions were optimized for each primer pair as follows. For human pIgR, we used 25 cycles at 94°C for 30 s, 58°C for 1 min, and 68°C for 2 min; final extension was 68°C for 7 min. For human IRF-1, it was 30 cycles at 95°C for 30 s, 55°C for 30 s, and 72°C for 1 min; final extension was 72°C for 10 min. For mouse pIgR, we used 30 cycles at 94°C for 45 s, 61°C for 45 s, and 72°C for 1.5 min; final extension was 72°C for 10 min. For mouse IRF-1, we used 23 cycles at 94°C for 45 s, 61°C for 45 s, and 72°C for 1.5 min; final extension was 72°C for 10 min. ß-actin primers were included with the pIgR or IRF-1 primers as an internal control. Amplified cDNA products were separated by electrophoresis in 2% agarose gels, visualized with the fluorescent dye SYBR Green 1 (FMC Bioproducts, Rockland, ME), and quantified by laser densitometry using a STORM Phosphoimager (Molecular Dynamics, Sunnyvale, CA). Each sample of HT-29v20 cells was analyzed using a range of concentrations of total cellular RNA as template (Fig. 1GoA). Regression lines were calculated for plots of fluorescence intensity (y-axis) vs input RNA (x-axis) (Fig. 1GoB). Normalized mRNA levels were calculated as the ratio of the y values for pIgR or IRF-1 to ß-actin at the midpoints of the linear ranges of the regression curves (r2 >= 0.9). Data shown are representative of two experiments. For mouse tissues, it was determined that a template concentration of 200 ng total cellular RNA would yield cDNA products for pIgR, IRF-1, and ß-actin that were within the linear range of amplification. Amplified cDNA products were separated by electrophoresis in 2% agarose, visualized with ethidium bromide, and quantified using National Institute of Health Image 1.6 software. Normalized mRNA levels were calculated by dividing the fluorescence intensities of the cDNA products for pIgR or IRF-1 by ß-actin.


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  		Table I. Primer pairs used in RT-PCR assays

 


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  		FIGURE 1. Quantitative RT-PCR assay for human pIgR mRNA. A, Amplified cDNA products were analyzed by agarose electrophoresis. B, Intensities of bands corresponding to pIgR (squares) and ß-actin (triangles) were quantified by densitometry and analyzed by linear regression. Normalized pIgR mRNA equals fluorescence intensity for pIgR/ß-actin at the midpoint of the linear regression curve.

 

   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Coordinate regulation of IRF-1 and pIgR mRNA in HT-29 human colon carcinoma cells by proinflammatory cytokines

To examine whether the human IRF-1 and PIGR genes are coordinately regulated by proinflammatory cytokines, we developed sensitive and quantitative RT-PCR assays for their mRNA products. A typical assay for pIgR mRNA in HT-29v20 human colon carcinoma cells is shown in Fig. 1Go. The responses of pIgR and IRF-1 mRNA to proinflammatory cytokines are shown in Fig. 2GoA. In the first experiment (high dose), HT29v20 cells were treated with IFN-{gamma}, TNF-{alpha}, and IL-1ß, alone and in combination, at doses that were determined to be optimal for up-regulation of pIgR by the individual cytokines (7, 10). In the second experiment (low dose), HT-29v20 cells were treated with the same combinations of cytokines at 1/20 of the doses used in the first experiment. Because cytokine induction of the IRF-1 gene precedes induction of the PIGR gene (13), cells were harvested at 12 h for analysis of IRF-1 mRNA and at 24 h for analysis of pIgR mRNA. To facilitate comparisons among cytokines, the treatment groups are arranged in order of increasing effects on pIgR mRNA and are grouped separately for treatments that did or did not include TNF-{alpha}.



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  		FIGURE 2. Correlation of IRF-1 and pIgR mRNA levels in cytokine-treated human colon carcinoma cells. Total cellular RNA was isolated from HT-29v20 cells cultured for 12 h (IRF-1) or 24 h (pIgR) in the presence of the indicated cytokines: 100 U/ml IFN-{gamma}, 10 ng/ml IL-1ß, and 10 ng/ml TNF-{alpha} (high dose) or 5 U/ml IFN-{gamma}, 0.5 ng/ml IL-1ß, and 0.5 ng/ml TNF-{alpha} (low dose). A, Relative levels of pIgR and IRF-1 mRNA were determined by RT-PCR. Values for pIgR or IRF-1 mRNA in unstimulated HT-29v20 cells are set at 1.0 to facilitate direct comparisons. B, Correlation analysis of pIgR and IRF-1 mRNA levels for cells treated with low doses of cytokines.

 
At high doses of cytokines, both IFN-{gamma} and IL-1ß caused a threefold increase in pIgR mRNA, and their effects were not additive. A different trend was observed for IRF-1 mRNA, where IFN-{gamma} caused a much greater increase (5.5-fold) than did IL-1ß (2.4-fold), and their effects appeared to be additive (7.2-fold). Conversely, the high dose of TNF-{alpha} caused a large increase in IRF-1 mRNA (7.2-fold) and only a moderate increase in pIgR mRNA (2-fold). In addition, the high dose of TNF-{alpha} inhibited the effects of IFN-{gamma} and IL-1ß on pIgR mRNA, but not IRF-1 mRNA. Somewhat different trends were observed at low cytokine concentrations. Treatment with low doses of IL-1ß or IFN-{gamma} alone resulted in very modest increases in pIgR mRNA (1.5-fold and 2.1-fold, respectively) and IRF-1 mRNA (1.3-fold and 1.9-fold, respectively), while the combination of IL-1ß and IFN-{gamma} was additive for pIgR mRNA (2.8-fold) and synergistic for IRF-1 mRNA (3.4-fold). Treatment with a low dose of TNF-{alpha} alone had no effect on pIgR mRNA and only a modest effect on IRF-1 mRNA (1.4-fold). However, TNF-{alpha} in combination with IFN-{gamma} or IL-1ß caused relative decreases in pIgR mRNA and synergistic increases in IRF-1 mRNA.

To determine whether the responses of IRF-1 and pIgR mRNA to proinflammatory cytokines were correlated, we subjected the data in Fig. 2GoA to linear regression and correlation analyses. At high doses of cytokines, there was no significant correlation between IRF-1 and pIgR mRNA levels (data not shown). At low doses of cytokines, however, IRF-1 and pIgR mRNA levels were clearly correlated (Fig. 2GoB). The correlation was most apparent if treatment groups that did not include TNF-{alpha} (no cytokines vs IFN-{gamma} and IL-1ß, alone and in combination) were analyzed separately from treatment groups that included TNF-{alpha} (alone and in combination with IFN-{gamma} and/or IL-1ß). While strong correlations were observed for both groups (r2 = 0.947 without TNF-{alpha}, r2 = 0.901 with TNF-{alpha}), the slope of the regression line was threefold higher in the absence than in the presence of TNF-{alpha} (slope = 0.74 vs 0.23).

Our data suggest a positive relationship between the regulation of the IRF-1 and PIGR genes by proinflammatory cytokines. High doses of IL-1ß may further increase pIgR mRNA, and TNF-{alpha} at any dose may decrease pIgR mRNA, by additional mechanisms that are independent of IRF-1. It should also be noted that the regression lines in Fig. 2GoB do not pass through the origin, suggesting that basal expression of pIgR mRNA in intestinal epithelial cells can occur in the absence of IRF-1. The conclusions of our in vitro studies are supported by in vivo studies in mice.

Expression of pIgR mRNA is reduced in IRF-1-deficient mice

We previously identified a binding site for IRF-1 in exon 1 of the human PIGR gene (13). Significantly, this IRF-1 site is 100% conserved in the human, rat, and mouse PIGR genes (Fig. 3GoA). We therefore hypothesized that expression of pIgR mRNA in mouse tissues is correlated with endogenous expression of IRF-1. To test this hypothesis, we measured levels of pIgR and IRF-1 mRNA in intestine, liver, and spleen of wild-type and IRF-1-deficient mice (Fig. 3GoB). Levels of pIgR mRNA in intestine and liver of IRF-1-deficient mice were reduced by 47% and 98%, respectively, compared with wild-type mice. These results suggest that mouse intestinal epithelial cells regulate pIgR expression by both IRF-1-dependent and -independent mechanisms, consistent with our findings in human intestinal epithelial cells (see above). In contrast, pIgR expression in mouse liver appears to be almost entirely dependent on IRF-1. No pIgR mRNA was detected in spleens of either wild-type or IRF-1-deficient mice, confirming the tissue specificity of pIgR expression. IRF-1 mRNA levels were approximately threefold higher in intestines than livers of wild-type mice, perhaps reflecting differences in endogenous cytokine levels between these tissues.



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  		FIGURE 3. Levels of pIgR mRNA are significantly reduced in intestines and livers of IRF-1-deficient mice. A, Interspecies conservation of the IRF-1 binding site in exon 1 of the human (13), rat (18), and mouse (19, 20) PIGR genes. B, Relative levels of pIgR and IRF-1 mRNA were determined by RT-PCR. Data are expressed as mean ± SEM for three wild-type B6 mice and five IRF-1-deficient mice. B.D., below detection. *, Significant differences between wild-type and IRF-1-deficient mice (p < 0.05).

 
A model for regulation of the PIGR gene by proinflammatory cytokines

A model for the molecular mechanisms of signaling through IRF-1 is presented in Fig. 4Go. IFN-{gamma}, IL-1ß, and TNF-{alpha} interact with their respective cell surface receptors to transduce a variety of signals, including the Janus kinase (JAK)/STAT (IFN-{gamma}) and NF-{kappa}B (IL-1ß and TNF-{alpha}) cascades. The STAT1 and NF-{kappa}B transcription factors are then translocated to the nucleus, where they enhance transcription of the IRF-1 promoter (reviewed in 15 . Newly synthesized IRF-1 is translocated to the nucleus and binds an element in exon 1 of the PIGR gene (13), leading to increased PIGR transcription and higher levels of pIgR mRNA. Low doses of cytokines caused synergistic induction at IRF-1, perhaps mediated by cooperative binding of STAT1 and NF-{kappa}B to the IRF-1 promoter (17). Such a mechanism could allow for optimal induction of pIgR expression by proinflammatory cytokines at low concentrations that would minimize damage to the intestinal epithelium. It should be noted that proinflammatory cytokines transduce a variety of signals in addition to IRF-1, which in the case of IL-1ß may stimulate pIgR expression and in the case of TNF-{alpha} may inhibit pIgR expression. Furthermore, noninflammatory cytokines such as IL-4 may enhance pIgR expression (5, 7, 9), either through up-regulation of IRF-1 or through IRF-1-independent pathways.



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  		FIGURE 4. A model for regulation of the PIGR gene by proinflammatory cytokines.

 


   Footnotes
 
1 Supported by National Institutes of Health Grant R01CA51998, U.S. Department of Education Grant P200A50092, and the University of Kentucky Research Fund. J.F.P. is the recipient of National Multiple Sclerosis Society Postdoctoral Fellowship FG-1173-A-1. Back

2 Address correspondence and reprint requests to Dr. Charlotte Kaetzel, Department of Pathology, MS117 Chandler Medical Center, University of Kentucky, Lexington, KY 40536. E-mail address: Back

3 Abbreviations used in this paper: pIgR, polymeric IgR; IRF, IFN regulatory factor. Back

Received for publication September 24, 1998. Accepted for publication November 25, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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