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The Journal of Immunology, 2001, 166: 5859-5863.
Copyright © 2001 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: FISP (IL-4-Induced Secreted Protein), a Novel Cytokine-Like Molecule Secreted by Th2 Cells1

Gabriele Schaefer, Chandrasekar Venkataraman2 and Ulrike Schindler

Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Th cell subsets, namely Th1 and Th2 cells, play an important role in mounting an immune response against invading pathogens. Several genes are selectively up-regulated during differentiation and effector phases of Th subsets. In this study, we report the identification of a novel cytokine-like molecule designated FISP (IL-4-induced secreted protein), which is selectively expressed and secreted by Th2 cells. Detectable levels of FISP are observed only 3 days after initiation of Th2 differentiation. Expression of FISP in developing Th cells requires at least two signals: TCR signaling involving protein kinase C activation and STAT6-dependent IL-4R signaling.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
T helper lymphocytes can be divided into at least two distinct subpopulations, type 1 (Th1) and type 2 (Th2) cells, based on their cytokine profile and their functional activities (1). Th1 cells produce IFN-{gamma} and IL-2 and provide protection against intracellular pathogens. Moreover, Th1 cells mediate delayed-type hypersensitivity and organ-specific autoimmune diseases (2). Th2 cells secrete IL-4 as well as IL-5, IL-6, IL-10, and IL-13, which in turn regulate the production of IgE and IgG1 in B cells, recruitment of eosinophils, and influence macrophage function. Therefore, Th2 cells play important roles in allergic and infectious diseases (1). Th1 and Th2 cells arise from a common naive CD4+ precursor (Thp). Depending on the Ag and more importantly the presence of specific exogenous cytokines, a unique genetic repertoire is activated that leads to the differentiation of Thp into Th1 or Th2 cells.

IL-12 activates the transcription factor STAT4 and promotes the differentiation of naive cells into Th1 effector cells. Mice lacking either the IL-12R {beta}1-chain or STAT4 have impaired Th1 responses (reviewed in Ref. 3). In contrast, IL-4 activates STAT6, which is the crucial mediator of Th2 differentiation. Mice that are deficient in either the IL-4R {alpha}-chain or STAT6 fail to develop Th2 cells (reviewed in Ref. 4).

Significant progress has been made in understanding the signals that are required for Th2 differentiation. However, it remains to be seen if all components necessary for the function and development of Th2 cells have been identified. We used the representational difference analysis (RDA)3 method to isolate genes that are selectively expressed in Th2 cells and may have important functions in Th2 cell development. In this report, we describe the identification of a novel gene that we designated FISP (IL-4-induced secreted protein). FISP is a cytokine-like secreted protein and has significant homology to the rat gene mob-5, also named c49a (5, 6), and the human gene melanoma differentiation-associated gene (mda-7) (7). FISP is selectively expressed in Th2 cells but not in Th1 cells, and expression of FISP requires signaling via both the TCR and IL-4R complex.


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

Female BALB/c and AKR/J mice were obtained from Taconic (Germantown, NY). STAT4- and STAT6-deficient mice have been described previously (8, 9). Animals between 4 and 6 wk of age were used for this study. The Th1 clone, AE7, as well as the Th2 cell clone, D10.G4, were kindly provided by Laurie Glimcher (Harward School of Public Health, Boston, MA) and cultured as previously described (10).

Representational difference analysis

In vitro differentiation of total splenocytes or enriched CD4+ cells was performed as previously described (8, 10). Poly(A)+ RNA was prepared from differentiated Th1 and Th2 cells using the Fast Track 2.0 kit (Invitrogen, Carlsbad, CA), and cDNA was synthesized by Superscript Choice System (Life Technologies, Gaithersburg, MD) using a combination of oligo(dT) and 50 ng of random primers. Th2 cDNA was used as tester and Th1 cDNA as driver to perform RDA according to the previously published procedure (11, 12). Briefly, two rounds of hybridizations were conducted using a ratio between tester and driver of 1:100, followed by a ratio of 1:800 for the second round of hybridization. Products were subcloned into pBluescript KS+ (Stratogene, La Jolla, CA) and further analyzed for differential expression.

Construct

Full-length FISP cDNA was isolated from a Th2-specific PCR select subtractive cDNA pool (10) and subcloned into the XbaI site of a pRK5 derived C-terminal flag mammalian expression vector (kindly provided by H. Wesche, Tularik, South San Francisco, CA). The cDNA sequence of full-length FISP was verified by RT-PCR of RNA derived from Th2 and D10.G4 cells.

Northern blot analysis

Total RNA was prepared using TRIzol (Life Technologies) according to the manufacturer’s instructions. Total RNA (10–15 µg) was fractionated on a formaldehyde gel and transferred to nylon membrane. A 302-bp fragment of FISP was obtained by PCR using the primers 6a (5'-GAGTTCCGATTTGGGTCTTGCCAAG) and 6b (5'-GGGCTGTAGTTGTGACATGATGAC) and was used for hybridization. RNA from different tissues was purchased from Ambion (Austin, TX). Hybridization was performed using ExpressHyb (Clontech Laboratories, Palo Alto, CA) according to the manufacturer’s protocol.

Western blot analysis

Approximately 3 x 107 of D10.G4 cells (maintained for over 3 mo in the presence of 10 ng/ml IL-2) were cultured for 12 h in serum-free RPMI 1640 medium. Conditioned medium was collected and concentrated 60-fold. Twenty microliters of conditioned medium was subjected to SDS-PAGE, and Western blot analysis was performed using a rabbit polyclonal anti-FISP Ab raised against aa 166–183 of the protein. Supernatant was also collected from cultured 293 cells, transiently transfected with FISP expression construct. For peptide competition experiments, anti-FISP was incubated with FISP peptide (aa 166–183) or control peptide in a 1:10 ratio (w/w) for 2 h at room temperature, before incubation with membrane.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
FISP is selectively expressed in lymphocytes under Th2 differentiation conditions

To identify genes that are differentially expressed in Th2 cells, we isolated total splenocytes and cultured them under Th1 and Th2 differentiation conditions (8). After 7 days of differentiation, total RNA was extracted and Th1- or Th2-specific cDNA pools were obtained. Th2-specific cDNAs were selected using the RDA method (11). A number of novel cDNAs were identified, and one of them, designated FISP, was further characterized.

The open reading frame of FISP encodes a protein of 220 aa with a predicted molecular mass of 25 kDa (Fig. 1Go). Blast analysis revealed that at DNA level FISP was 89% identical with rat mob-5 (also designated as c49a) and 80% identical with human mda-7. At the protein level, FISP shares 93% identity with mob-5/c49a and 69% identity with mda-7. To a lesser degree, FISP showed homology to IL-10 (33%) and the recently described IL-20 (13) (30%), suggesting that FISP has a cytokine-like structure. Analysis with the program SignalP (14) revealed a potential signal peptide sequence from aa 1–65.



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  		FIGURE 1. Alignment of the FISP amino acid sequence with mob-5, mda-7, mouse IL-10, and mouse IL-20. The cDNA of FISP encodes a protein of 220 aa containing a predicted signal sequence cleavage site between position 65 and 66. Conserved amino acids are highlighted in bold.

 
Th2-specific expression of FISP was confirmed by Northern blot analysis. FISP transcripts were exclusively seen in Th2 lymphocytes but not in Th1 lymphocytes or untreated splenocytes (Fig. 2GoA). As expected, IL-18R was differentially expressed in Th1 cells. A more detailed kinetic analysis revealed that FISP mRNA was first detected in cells differentiated for 3 days, with highest RNA levels seen at day 5 (Fig. 2GoB). FISP transcripts were not detected at any time when cells were cultured under Th1 conditions.



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  		FIGURE 2. Th2-specific expression of FISP. A, Total RNA was isolated from splenocytes either unstimulated (lane 1) or stimulated with anti-CD3, IL-12, and anti-IL-4 (lane 2, Th1 condition) or IL-4 and anti-IL-12 (lane 3, Th2 condition), and subjected to Northern blot analysis using a FISP-specific probe. The blot was stripped and reprobed for {beta}-actin. An IL-18R-specific probe was used to verify the differentiation of Th1 cells (lane 2). B, Up-regulation of FISP during in vitro differentiation of Th2 cells. Cells were stimulated under Th1 or Th2 conditions for indicated time periods, and Northern blot analysis was performed as described above.

 
FISP RNA was not detected in any of the multiple tissues tested. However, FISP transcripts were readily detected in anti-CD3-activated D10.G4 cells (Th2 clone) (Fig. 3Go). Additionally, activation of thymocytes with PHA plus IL-4 plus IL-1, splenocytes with anti-IgM (with or without IL-4) or anti-CD40 (with or without IL-4), or a murine macrophage cell line (RAW 264.7) treated with LPS (with or without IL-4) did not initiate expression of FISP (data not shown). Taken together, this data indicate that the expression of FISP is extremely restricted and only seen in activated T cells.



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  		FIGURE 3. Tissue distribution of FISP. Total RNA from multiple tissues (25 µg each) and 2 µg of total RNA from anti-CD3-activated D10.G4 cells were subjected to Northern blot analysis using a FISP-specific probe. The autoradiograph was exposed at -80°C for 5 days. Ethidium bromide-stained ribosomal RNA was used to show equal loading.

 
FISP expression is induced in CD4+-enriched Th2 cells and is not inhibited in Th1 cells

Splenocytes are composed of a number of different cell types. Therefore, we wished to verify differential expression of FISP in CD4+-enriched Th subsets. When CD4+ T cells were stimulated under Th2 conditions, FISP expression was detected. Interestingly, T cells cultured under neutral conditions (anti-CD3 and IL-2) also expressed FISP mRNA. No transcripts were observed in Th1 cells (Fig. 4GoA). These data suggested that expression of FISP might be inhibited in Th1 cells. Hence, we tested whether IL-12 or IFN-{gamma} can down-regulate FISP expression in developing Th1 cells. Because STAT4 is a major player in the IL-12 signaling pathway, leading to the differentiation of Th1 cells (9), we studied FISP expression in STAT4- deficient T cells cultured under Th1, Th2, and neutral conditions. We also examined IFN-{gamma}-deficient mice for FISP expression under Th1 or Th2 conditions. Fig. 4GoB shows that expression of FISP in STAT4- or in IFN-{gamma}-deficient mice was identical with the expression pattern seen in wild-type mice. This indicates that FISP was not actively repressed in Th1 cells by the IL-12-dependent factor STAT4 or by the presence of IFN-{gamma}.



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  		FIGURE 4. Expression of FISP in CD4+-enriched cells. A, Enriched CD4+ cells from wild-type mice were stimulated for 7 days under neutral (lane 1), Th1 (lane 2), or Th2 (lane 3) differentiation conditions and subjected to Northern blot analysis as described above. Enriched CD4+ cells from STAT4 (B)- or STAT6 (C)-deficient mice or splenocytes from IFN-{gamma}-deficient mice (B) were stimulated and subjected to Northern blot analysis as described in A. D, Enriched CD4+ cells from wild-type mice were stimulated for 6 days with anti-CD3 in the presence of either 50 µg/ml isotype control IgG (lane 1) or 50 µg/ml neutralizing anti-IL-4 Ab (lane 2) and subjected to Northern blot analysis.

 
Because FISP was detected in activated T cells, we examined whether IL-4 signaling is required for the selective expression of FISP in Th2 cells. STAT6 is known to be essential for the IL-4-induced differentiation of Th2 cells (8, 15, 16). Therefore, we determined the expression of FISP in differentiated CD4+ T cells derived from STAT6-deficient mice. As expected, no expression was seen in cells treated under Th1 conditions. STAT6-deficient CD4+ cells, which were differentiated under Th2 or neutral conditions, also lacked FISP expression. These data suggest a direct correlation between IL-4-mediated signaling and FISP up-regulation (Fig. 4GoC).

Because FISP mRNA was detected under neutral conditions in wild-type but not in STAT6-deficient T cells, we tested whether IL-4 signaling occurred at low levels under neutral culture conditions. Enriched wild-type CD4+ cells were treated for 5 days with anti-CD3 plus IL-2 in the presence of an anti-IL-4 Ab or a control Ab. Fig. 4GoD shows that the presence of anti-IL-4 completely abolished FISP expression (lane 2), whereas incubation with the control Ab had no effect (lane 1). These data indicate that FISP is differentially expressed in Th2 cells and in IL-4-producing T cells developed under neutral conditions. The latter finding correlates with earlier studies showing that activated T cells derived from BALB/c mice produce IL-4 under neutral culture conditions (17). Taken together, the data indicate that FISP is an IL-4-inducible gene that is activated by STAT6.

Elevated levels of FISP transcripts are present in activated D10.G4 cells

We further analyzed if FISP was also differentially expressed in established Th1 and Th2 cell lines. FISP expression was not seen in untreated D10.G4 cells (Fig. 5GoA, lane 1) or AE7 cells (data not shown). However, FISP mRNA was strongly up-regulated upon activation of D10.G4 cells with plate-bound anti-CD3. Maximal levels were observed after 3 h of stimulation. Anti-CD3 stimulation of AE7 cells in the presence or absence of IL-4 did not up-regulate FISP expression (Fig. 5GoA, lanes 7 and 8). These data support the notion that FISP is selectively expressed in Th2 cells. Interestingly, in long-term cultures of D10.G4 (>3 mo), FISP was constitutively expressed, even in the absence of anti-CD3 (data not shown), suggesting that FISP expression may be influenced by the proliferation conditions of D10.G4 cells.



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  		FIGURE 5. Expression of FISP in a Th2 cell clone D10.G4. A, D10.G4 and AE7 cells were stimulated for 3 h or as indicated, and Northern blot analysis was performed as described above. B, D10.G4 were unstimulated (lane 1), stimulated with anti-CD3 (lane 2), mezerein (10 ng/ml, lane 3), or mezerein plus IL-4 (lane 4) for 3 h. Total RNA was prepared and subjected to Northern blot analysis using a FISP- or IL-4-specific probe. Culture supernatants were collected, and IL-4 secretion was measured by ELISA (R&D Systems, Minneapolis, MN). C, FISP is a secreted protein. Conditioned medium was collected from D10.G4 cells and transiently transfected 293 cells. Western blot analysis was performed as described in Materials and Methods. Arrows indicate FISP protein, and asterisks indicate a nonspecific high molecular mass band.

 
Regulation of FISP expression by TCR and IL-4

Protein kinase C (PKC) is one of the downstream signaling molecules in the TCR activation pathway. Mezerein is a nonphorbol ester and activates PKC. Human mda-7 was originally found in melanoma cells treated with IFN-{beta} and mezerein (7). To examine whether mezerein also induced FISP expression in D10.G4 cells, we treated cells with anti-CD3, mezerein, or mezerein plus IL-4 for 3 h and performed Northern blot analysis. Mezerein or IL-4 treatment did not induce FISP expression (Fig. 5Go, B, lane 3 and A, lane 2). However, treatment with mezerein plus IL-4 resulted in elevated FISP expression, similar to the levels seen with anti-CD3-treated cells (Fig. 5GoB). One explanation for this data might be that anti-CD3 treatment induces IL-4 production in D10.G4 cells, which, in turn, can positively regulate expression of FISP. In fact, stimulation of D10.G4 with anti-CD3 but not mezerein induced IL-4 production (Fig. 5GoB). Taken together, our data show that FISP expression requires a combination of at least two different signaling pathways, TCR engagement and IL-4 stimulation (Fig. 6Go).



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  		FIGURE 6. Activation model. Expression of FISP requires the presence of two different signaling pathways, intact TCR signaling via PKC and signaling through the IL-4 transduction pathway.

 
FISP is a secreted protein

Amino acid analysis using the program SignalP (14) predicted a signal sequence spanning from amino acids 1 to 65 with a potential cleavage site between aa 65 and 66, which suggested that FISP could be a secreted protein. Hence, we investigated whether D10.G4 cells secrete FISP. Western blot analysis of conditioned medium of long-term cultured D10.G4 cells revealed multiple bands, the most intense one with an approximate molecular mass of 27 kDa. This band was absent when blocking peptide was included in the Western analysis (Fig. 5GoC, lane 2). The specificity of blocking peptide and FISP Ab was confirmed in transiently transfected 293 cells (lanes 3–6). The lower migrating form of FISP may represent a differentially glycosylated or degraded form of the protein. As expected, FISP protein was not detected in conditioned medium from anti-CD3-treated AE7 cells (data not shown).

Recently, it was shown that overexpression of rat mob-5 as well as human mda-7 also leads to the secretion of these proteins into the culture medium (5). The high sequence similarity to mob-5 and mda-7 suggests that FISP might be the mouse homologue of these two genes. Overexpression of mda-7 in breast cancer cells appears to be proapoptotic and is involved in growth arrest (18). In contrast, expression of mob-5 is activated through ras and may play an important role in ras oncogene-mediated neoplasia (5). However, these functional differences suggest that FISP, mda-7, and mob-5 are not homologues but represent closely related members of a gene family with distinct functions. Further studies are necessary to address the function of FISP during Th1/Th2 differentiation.


   Acknowledgments
 
We thank Monique Kuhn for excellent technical assistance and Tim Hoey for helpful discussions and comments.


   Footnotes
 
1 The nucleotide sequence reported in this paper has been submitted to the GenBank/EBI Data Bank with accession number AF333251. Back

2 Address correspondence and reprint requests to Dr. Chandrasekar Venkataraman, Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080. Back

3 Abbreviations used in this paper: RDA, representational difference analysis; FISP, IL-4-induced secreted protein; mda, melanoma differentiation-associated gene; PKC, protein kinase C. Back

Received for publication November 28, 2000. Accepted for publication March 22, 2001.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
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