Type I IFNs, IFN-α, -β, and -ω, are cytokine family members with multiple immune response roles, including the promotion of cell growth and differentiation. Conversely, the type I IFNs are potent inhibitors of IL-7-dependent growth of early B lineage progenitors, effectively aborting further B lineage differentiation at the pro-B cell stage. Type I IFNs α and β function via receptor-mediated activation of a Jak/Stat signaling pathway in which Stat-1 is functionally important, because many IFN-induced responses are abrogated in Stat-1-deficient mice. To the contrary, we show here that the inhibition of IL-7-dependent B lymphopoiesis by IFN-αβ is unaffected in Stat-1-deficient mice. The present data indicate that the type I IFNs can activate an alternative signaling pathway in which neither Stat-1 nor phosphatidylinositol 3′-kinase are essential components.

Bcell development proceeds in an orderly fashion in the bone marrow (BM)3 wherein the different differentiation stages can be characterized by the rearrangement status of the Ig genes and the expression of discriminating cell surface markers (1). In mice, the expression profiles of CD45/B220, CD43 (leukosialin), BP-1/6C3 (aminopeptidase A), and μ heavy chains allow the discrimination of pro-B cells (B220+CD43+BP-1IgM) and pre-B cells (B220+CD43+/−BP-1+IgM) (2, 3, 4). Pre-B cells also may express a receptor formed by μ heavy chains and the surrogate light chain proteins VpreB and λ5 (5). Productive light chain gene rearrangement occurs in postmitotic pre-B cells (6), and the subsequent expression of an IgM receptor characterizes the immature B cell (B220+CD43BP-1+IgM+). Finally, coexpression of IgD begins when the newly formed B cells migrate to the periphery (7).

IL-7, an essential growth factor for B and T lymphopoiesis in mice (8), may also influence the rearrangement of B and TCR genes (9, 10). The IL-7 receptor is composed by the IL-7Rα-chain and the common γ-chain, which is shared by the IL-2, IL-4, IL-9, and IL-15 receptors (11). In keeping with the onset of IL-7 receptor expression in pro-B cells (9), B cell development is blocked at this differentiation stage in mice deficient in either IL-7 or its receptor (12, 13).

The type I IFNs, IFN-α, -β, and -ω, are members of a family of pleiotropic cytokines that participate in antiviral responses as well as in other physiological processes, such as cell growth and differentiation (14). In earlier studies, we found that the type I IFNs selectively inhibit IL-7 promoted growth of early B lineage and T lineage cells, whereas having no effect on cell growth induced by other cytokines (15, 16). The IFN-αβ inhibition of IL-7-dependent cells or cell lines is featured by the induction of apoptosis. Because type I IFNs have been shown to be constitutively produced by resident BM macrophages (15), they could play a regulatory role in normal B cell development.

IFNs bind to their cell surface receptors to activate the Jak-Stat signaling system (17, 18, 19). Janus family kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2) are closely related cytoplasmic tyrosine kinases that constitutively associate with the α- and β-chains of the type I IFN receptor (IFNAR). Receptor interaction with IFN-α or -β promotes Jak1 and Tyk2 phosphorylation of tyrosine residues and activates the signal activating and transcription factors Stat-1, Stat-2, and Stat-3. The Stat proteins thereby acquire the capacity to oligomerize whereupon they migrate into the nucleus and bind to regulatory motifs in the promoter regions of many genes to modulate their transcription (20). IL-7 signaling activates a partially overlapping Jak-Stat signaling pathway. Both the Jak1 and Jak3 kinases are activated after IL-7 receptor ligation, and these kinases phosphorylate multiple substrates, including the Stat-1 and the Stat-5 transcription factors (21). However, among the multiple components of the type I IFN activation pathway, Stat-1 appeared essential in that all IFN-induced responses originally examined were defective in Stat-1-deficient mice (22, 23). Nevertheless, this assumption can be questioned because alternative IFN signaling pathways have been identified (14, 20)

The inhibition of B and T lymphopoiesis by type I IFNs could reflect cross-talk between the type I IFN and IL-7 signaling pathways (15, 16). As a first step in examining this interaction, we examined the effects of IFN on IL-7-mediated B lymphopoiesis in Stat-1-deficient mice. Contrary to our expectation, Stat-1 does not appear to be essential for the IFN inhibition of IL-7-promoted B lymphopoiesis.

FITC-labeled mAbs to S7/CD43, Sca-1 and IgD, PE-labeled Abs to B220 and BP-1, CyChrome-labeled Abs to CD19 and μ heavy chains, and biotin-labeled Abs to the IL-7Rα-chain were obtained from PharMingen (San Diego, CA); streptavidin (SA)-CyChrome and SA-PE were obtained from Southern Biotechnology Associates (Birmingham, AL). Cell suspensions were incubated on ice for 25 min with the FITC-, PE-, CyChrome-, or biotin-conjugated mAbs, washed with PBS containing 3% FCS and 0.02% NaN3, and counterstained with SA-CyChrome or SA-PE to reveal biotin conjugates. Before analysis with a Becton Dickinson (Mountain View, CA) FACScalibur flow cytometer, 1 μg/ml propidium iodide in PBS was added to allow identification of dead cells for exclusion from the analysis. The data was analyzed with the WinMDI 2.8 (Trotter@scripps.edu) software program.

Stat-1- (22) and Ifnar1-deficient mice (B&K Universal Group, North Humberside, U.K.) were of 129Sv/Ev background. Although the type I IFN receptor (IFNAR) is formed by two chains, IFNAR1 and IFNR2, IFN-αβ-induced responses were undetectable in Ifnar1−/− mice (16). Stat-1 mice were bred as −/− male × +/− female to derive +/− and −/− littermates. BALB/c mice were bred at our animal facility at the University of Alabama (Birmingham, AL). Four- to 6-wk-old animals were used as BM donors, and fetal liver cells were obtained 15 days postcoitus. Stat-1 genotyping was conducted on DNA samples from tails or whole embryos, employing a PCR-based analysis with previously described primers (22).

The Scid7 IL-7-dependent cell line, a gift from Dr. S. I. Nishikawa (Kyoto University, Kyoto, Japan), has a pro-B phenotype (CD19+CD43+BP-1+μHC) and is sensitive to IL-7 deprivation and the inhibitory effect of IFN-αβ (15).

An IFN-α and -β (IFN-αβ) combination isolated from viral-infected cultures and control supernatants from mock-infected cultures were purchased from Access Biomedical (San Diego, CA) and used at an equivalent concentration of 103 U/ml.

BM mononuclear cells from 6- to 8-wk-old mice or fetal liver mononuclear cells from 15-day-old embryos were cultured with IL-7-transfected NIH3T3 fibroblasts (24) at a concentration of 106 cells/ml in RPMI 1640 medium with 5% FCS, l-glutamine, penicillin/streptomycin, and 50 μM 2-ME in the presence or absence of IFN-αβ. Ly294002 and wortmannin inhibitors were obtained from Calbiochem (La Jolla, CA). Cultured cells were harvested by treatment with 0.02% EDTA, and viable lymphoid cells were enumerated by phase microscopy on the basis of trypan blue exclusion.

Abnormalities of B lymphopoiesis have not been noted in Stat-1−/− mice (22, 23), but a detailed analysis of B lineage development in these mice has not been reported. Therefore, in our initial studies, we examined B lineage cells for the expression of B220, CD19, CD43, BP-1, IgM, and IgD in BM samples from Stat-1−/− mice and their +/− littermate controls at 4–6 mo of age. This comparative analysis confirmed the expectation that B cell development occurs normally in Stat-1-deficient mice (data not shown).

The possible role of Stat-1 in the IFN-αβ-mediated inhibition of B cell development was tested initially in an ex vivo system wherein progenitor cells from adult BM or fetal liver are cultivated with IL-7-transfected fibroblasts. In this ex vivo model, B220 progenitor cells undergo proliferation and progressive differentiation into IgM+ B cells, whereas untransfected fibroblasts do not support B cell development (data not shown). Contrary to our expectation, in these experiments, the growth of B220+ B lineage cells was inhibited by IFN-αβ treatment regardless of the Stat-1 genotype. Comparable reductions in the numbers of viable B220+ cells were observed in IFN-treated cultures of cells from the Stat-1+/− and Stat-1−/− mice (Fig. 1). Phenotypic analyses over the 7-day culture interval further indicated comparable cellular composition of the surviving cell populations (Fig. 2). Notably, the development of μHC+ pre-B and B cells was profoundly inhibited by IFN-αβ regardless of whether the progenitor cells were obtained from Stat-1+/− or from Stat-1−/− mice. The number of B220 cells was also reduced by the IFN-αβ treatment, although the limited growth of non-B lineage cells in this ex vivo system made it difficult to discern whether this was a primary or secondary effect. Titration of the IFN dosage resulted in a graduated decrease in the inhibition with lower concentrations, but differential levels of inhibition were not evident for the Stat-1+/− and Stat-1−/− cells at any IFN concentration (not shown). In keeping with previous results obtained for IL-7-dependent cell lines (15), the levels of IL-7R expression were not reduced after IFN-αβ treatment, indicating that the inhibition cannot be explained simply by deprivation of the IL-7 signal (not shown).

FIGURE 1.

IFN-αβ inhibition of IL-7-dependent B lymphopoiesis in Stat-1+/− and −/− mice. A, Adult BM cells from Stat-1+/− and Stat-1−/− mice were cultured on IL-7-transfected fibroblasts for 4 days in the presence or absence of IFN-αβ. Viable cells were identified by trypan blue exclusion, counted, and the percentage of viable B lineage cells (B220+PI) was determined by immunofluorescence flow cytometry. Results of three separate experiments are indicated. B, Progenitor cells in the liver of 15-day-old embryos, either Stat-1+/− or Stat-1−/−, were cultured and analyzed in the same manner as for BM cultures. Four embryos of each genotype were used in this experiment. These results were reproduced in five separate experiments. The numbers of B220+ cells (±SE) recovered per 106 BM (A) or fetal liver (B) cells initially cultured are indicated (∗, p < 0.01).

FIGURE 1.

IFN-αβ inhibition of IL-7-dependent B lymphopoiesis in Stat-1+/− and −/− mice. A, Adult BM cells from Stat-1+/− and Stat-1−/− mice were cultured on IL-7-transfected fibroblasts for 4 days in the presence or absence of IFN-αβ. Viable cells were identified by trypan blue exclusion, counted, and the percentage of viable B lineage cells (B220+PI) was determined by immunofluorescence flow cytometry. Results of three separate experiments are indicated. B, Progenitor cells in the liver of 15-day-old embryos, either Stat-1+/− or Stat-1−/−, were cultured and analyzed in the same manner as for BM cultures. Four embryos of each genotype were used in this experiment. These results were reproduced in five separate experiments. The numbers of B220+ cells (±SE) recovered per 106 BM (A) or fetal liver (B) cells initially cultured are indicated (∗, p < 0.01).

Close modal
FIGURE 2.

IFN-αβ-mediated inhibition of B lymphopoiesis in IL-7 supported cultures of fetal liver progenitors from Stat-1+/− and Stat-1−/− mice. Fetal liver cells were cultured on IL-7-transfected fibroblasts before harvesting for immunofluorescence analysis as in Fig. 1. The results of this experiment were confirmed in five separate experiments.

FIGURE 2.

IFN-αβ-mediated inhibition of B lymphopoiesis in IL-7 supported cultures of fetal liver progenitors from Stat-1+/− and Stat-1−/− mice. Fetal liver cells were cultured on IL-7-transfected fibroblasts before harvesting for immunofluorescence analysis as in Fig. 1. The results of this experiment were confirmed in five separate experiments.

Close modal

To confirm the specificity of the IFN-αβ inhibitory effect, we examined progenitor cells from mice deficient in the type I IFN receptor (Ifnar1−/−). In these experiments, fetal liver cells from Stat-1+/− and Ifnar1−/− mice were cultured with the IL-7-producing fibroblasts either in the presence or absence of IFN-αβ. Whereas IFN-αβ inhibited the development of Stat-1+/− progenitors, the development of B lineage cells from the Ifnar1−/− progenitors was unaffected by IFN-αβ treatment (Fig. 3). These results indicate that the IFN-αβ inhibitory effect is mediated specifically via the type I IFN receptor and cannot be attributed to a nonspecific toxin in the IFN-αβ preparation.

FIGURE 3.

Analysis of the IFN-αβ effect on B lymphopoiesis in type I receptor-deficient mice (Ifnar1−/−). Fetal liver cells from Stat-1+/− and Ifnar1−/− mice were cultured for 4 days in the presence or absence of IFN-αβ before enumeration and immunofluorescence analysis as in Figs. 1 and 2. The results of this experiment were reproduced in three similar experiments.

FIGURE 3.

Analysis of the IFN-αβ effect on B lymphopoiesis in type I receptor-deficient mice (Ifnar1−/−). Fetal liver cells from Stat-1+/− and Ifnar1−/− mice were cultured for 4 days in the presence or absence of IFN-αβ before enumeration and immunofluorescence analysis as in Figs. 1 and 2. The results of this experiment were reproduced in three similar experiments.

Close modal

The foregoing evidence indicating that Stat-1 is nonessential for the type I IFN-induced inhibition of IL-7-induced B lymphopoiesis was surprising, given that Stat-1 is essential for all of the IFN-αβ responses assessed in mature B cells (23). In view of this paradox, we examined whether Stat-1 was essential for another type of IFN response in the fetal liver progenitors, namely the up-regulation of transcription and expression of the Sca-1 Ag (Ly-6A/E), a cell surface accessory molecule expressed on BM and fetal liver cells (25, 26). When we examined Sca-1 expression by early B lineage cells, an IFN-induced up-regulation of this Ag could be easily detected for cells from the Stat-1+/− mice, but not for cells from the Stat-1−/− animals. IFN-αβ also failed to enhance the expression of this Ag on cells from Ifnar1−/− mice, thereby confirming the IFN-αβ specificity of this response (Fig. 4). Therefore, this type I IFN response is Stat-1-dependent in B cell progenitors as is the case for B cells.

FIGURE 4.

Effect of IFN-αβ treatment on Sca-1 expression by B lineage cells. Fetal liver cells from Stat-1+/−, Stat-1−/−, and Ifnar1−/− mice were cultured for 4 days as indicated in Fig. 1 before immunofluorescence analysis of Sca-1 expression by B220+ cells.

FIGURE 4.

Effect of IFN-αβ treatment on Sca-1 expression by B lineage cells. Fetal liver cells from Stat-1+/−, Stat-1−/−, and Ifnar1−/− mice were cultured for 4 days as indicated in Fig. 1 before immunofluorescence analysis of Sca-1 expression by B220+ cells.

Close modal

PI 3′-kinase, which is involved in many signaling cascades that influence cell growth, is also activated following type I IFN stimulation (27, 28, 29). To examine its possible influence in the growth inhibition induced by IFN-αβ, we examined the role of PI 3′-kinase in the IFN-mediated inhibition of B lymphopoiesis. The initial assessment was conducted by adding Ly294002, an inhibitor of PI 3′-kinase (30), to cultures of fetal liver cells from BALB/c mice. Although relatively high concentrations of Ly294002 could inhibit B lymphopoiesis, this PI 3′-kinase inhibitor had no demonstrable counter effect on the IFN-mediated inhibition of cell growth at any of the concentrations employed (Fig. 5,A). The effect of this PI 3′-kinase inhibitor was also evaluated in experiments in which an IL-7-dependent pro-B cell line, Scid7, was cultured with IL-7. In these experiments, the Scid7 cells were inhibited by IFN-αβ at all inhibitor concentrations tested. Ly294002 alone was again inhibitory at the highest concentrations employed, but had no demonstrable counter effect on the IFN-αβ-mediated inhibition (Fig. 5 B). Wortmannin, another inhibitor of PI 3′-kinase, was also tested in these experiments with the same outcome (data not shown). The inhibitory effect of Ly294002 alone, most evident at the highest concentration employed (1 μM), can be attributed to the compromise of IL-7 signaling that involves PI 3′-kinase activity (10). If the IFN-αβ-mediated inhibition of cell growth also required PI 3′-kinase activity, an increase would be expected in the numbers of cells treated with both IFN-αβ and the inhibitor Ly290042. This outcome was not observed at any Ly290042 concentration, thereby suggesting that integrity of the PI 3′-kinase signaling pathway is not essential for the type I IFN-mediated inhibition of B lymphopoiesis.

FIGURE 5.

Analysis of the effect of the PI 3′-kinase inhibitor, Ly290042, on IFN-αβ-mediated inhibition of B lymphopoiesis. A, Fetal liver progenitors from E15 BALB/c embryos were cultured for 3 days with IL-7-transfected fibroblasts before treatment for 2 days with the inhibitor at different concentrations, in the presence or absence of IFN. B, Scid7 cells were cultured for 4 days in IL-7-containing media with or without the inhibitor and IFN-αβ before enumeration and analysis as in previous figures. Cell numbers correspond to pooled cells from four separate cultures and are representative of two independent experiments.

FIGURE 5.

Analysis of the effect of the PI 3′-kinase inhibitor, Ly290042, on IFN-αβ-mediated inhibition of B lymphopoiesis. A, Fetal liver progenitors from E15 BALB/c embryos were cultured for 3 days with IL-7-transfected fibroblasts before treatment for 2 days with the inhibitor at different concentrations, in the presence or absence of IFN. B, Scid7 cells were cultured for 4 days in IL-7-containing media with or without the inhibitor and IFN-αβ before enumeration and analysis as in previous figures. Cell numbers correspond to pooled cells from four separate cultures and are representative of two independent experiments.

Close modal

The present studies indicate that Stat-1 is not essential for the IFN-αβ-mediated inhibition of B lymphopoiesis, in contrast with previously described biological models wherein type I IFN-induced growth inhibition was abolished in Stat-1-deficient mice and cell lines (22, 23, 31).

Two major transcription factor complexes are formed in response to ligation of the type I IFN receptor: IFN-γ activation factor (GAF) and IFN-stimulated gene factor 3 (ISGF3) (17, 19, 20). GAF is a Stat-1 homodimer, whereas ISGF3 is formed by activated Stat-1, Stat-2, and p48 (32). Although Stat-1-deficient mice cannot form GAF, the possibility of a hypothetical ISGF3 complex lacking Stat-1 but still functional cannot be excluded for at least some responses. In this regard, we found that the expression of Sca-1, a gene containing targets for both GAF and ISGF3 factors in its promoter (26), was not up-regulated in B cell progenitors following IFN treatment of Stat-1-deficient mice.

The role of Stat-3 in type I IFN signaling is not as well documented as that for Stat-1 in part because the Stat-3 knockout is early embryonically lethal (33). Stat-3 may also be involved in the antiviral and antiproliferative activities of type I IFNs through up-regulation of NF-κB binding activity (34) and by functioning as an adapter to couple PI 3′-kinase to the IFN receptor, thereby activating a new signaling pathway (28, 29). PI 3′-kinase is also associated with IL-7 receptor signaling, and its activity is required for the proliferative response of B cell progenitors (10). The essential role of this signaling component is evidenced by the block in B lymphopoiesis at the pro-B cell stage in PI 3′-kinase-deficient mice (35, 36). Using inhibitors of PI-3′-kinase, Ly294002 and wortmannin, we were unable to alter the inhibitory effect of IFN-αβ. Nevertheless, the possibility of competition between IL-7 and IFN signaling pathways for the available pool of PI 3′-kinase was not tested in these experiments.

The indication that Stat-1 is not essential for the inhibition of B lymphopoiesis by type I IFNs suggests that another, as yet uncharacterized, transcription complex (lacking Stat-1) or a different IFN signaling pathway is responsible for this inhibition of B cell development. Interferons can inhibit the growth of embryonic fibroblasts in a Stat-1-dependent fashion involving regulation of c-myc expression. In this model system IFN-γ was recently shown to suppress c-myc expression in cells from wild-type mice, but not in those from Stat-1−/− mice (37). Indeed, in the Stat-1-deficient cells both c-myc and c-jun expression were rapidly up-regulated in response to IFN-γ, thereby providing evidence for Stat-1-independent signaling in cells of another differentiation pathway.

As components of the innate immune system, IFNs are produced in response to external aggression (14). They also may be constitutively produced in a normal organism. IFN-β is one of many lymphopoietic regulatory factors (reviewed in Ref. 38) produced locally in normal BM (15), where it may play a role in selection of the B cell repertoire (39). Dissociation between the IFN-induced antiviral and growth signaling pathways has also been described (40). The complexity of the IFN signaling cascades, together with the results described above, suggest an interesting versatility in the signaling components responsible for the rich diversity of IFN responses. Elucidation of the Stat-1-independent pathway that is activated in early B lineage cells via the type I IFN receptor may also reveal the mechanism whereby this signaling pathway counteracts with that of the IL-7 receptor.

1

This work was supported in part by National Institutes of Health Grant AI39816. R.G. was supported by a fellowship from the Human Frontier Science Program. M.D.C. is a Howard Hughes Medical Institute Investigator.

3

Abbreviations used in this paper: BM, bone marrow; Jak, Janus-activated kinase; IFNAR, type I IFN receptor; SA, streptavidin; PI, phosphatidylinositol; GAF, IFN-γ activation factor; ISGF3, IFN-stimulated gene factor 3.

1
Osmond, D. G., A. Rolink, F. Melchers.
1998
. Murine B lymphopoiesis: toward a unified model.
Immunol. Today
19
:
65
2
Cooper, M. D., D. Mulvaney, A. Coutinho, P. A. Cazenave.
1986
. A novel cell surface molecule on early B-lineage cells.
Nature
321
:
616
3
Hardy, R. R., C. E. Carmack, S. A. Shinton, J. D. Kemp, K. Hayakawa.
1991
. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow.
J. Exp. Med.
173
:
1213
4
Allman, D. M., S. E. Ferguson, V. M. Lentz, M. P. Cancro.
1993
. Peripheral B cell maturation. II. Heat-stable antigen (hi) splenic B cells are in immature developmental intermediate in the production of long-lived marrow-derived B cells.
J. Immunol.
151
:
4431
5
Karasuyama, H., A. Kudo, F. Melchers.
1990
. The proteins encoded by the VpreB and λ5 pre-B specific genes can associate with each other and with μ heavy chain.
J. Exp. Med.
172
:
969
6
Coffman, R. L., I. L. Weissman.
1983
. Immunoglobulin gene rearrangement during pre-B cell differentiation.
J. Mol. Cell. Immunol.
1
:
31
7
Vitetta, E. S., J. W. Uhr.
1976
. Cell surface immunoglobulin. XV. The presence of IgM and an IgD-like molecule on the same cell in murine lymphoid tissue.
Eur. J. Immunol.
6
:
140
8
Namen, A. E., S. Lumpton, K. Hjerrild, J. Wignall, D. Y. Mochizuki, A. Schmierer, B. Mosley, C. J. March, D. Urdal, S. Gillis.
1988
. Stimulation of B-cell progenitors by cloned murine interleukin-7.
Nature
333
:
571
9
Sudo, T. S., S. Nishikawa, N. Ohno, N. Akiyama, M. Tamakoshi, H. Yohida, S. I. Nishikawa.
1993
. Expression and function of the interleukin 7 receptor in murine lymphocytes.
Proc. Natl. Acad. Sci. USA
90
:
9125
10
Corcoran, A. E., F. M Smart, R. J. Cowling, T. Crompton, M. J. Owen, A. R. Venkitaraman.
1996
. The interleukin-7 receptor α chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis.
EMBO J.
15
:
1924
11
Ihle, J. N..
1995
. Cytokine receptor signaling.
Nature
377
:
591
12
Von Freeden-Jeffry, U., P. Vieira, L. A. Lucian, T. McNeil, S. E. G. Burdach, R. Murray.
1995
. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a non redundant cytokine.
J. Exp. Med.
181
:
1519
13
Peschon, J. J., P. J. Morrisey, K. H. Grabstein, F. J. Ramsdell, E. Maraskovsky, B. C. Gliniak, L. S. Park, S. F. Ziegler, D. E. Williams, C. B. Ware.
1994
. Early lymphocyte expansion is severely impaired in interleukin-7 receptor-deficient mice.
J. Exp. Med.
180
:
1955
14
A. W. Thomson, ed.
The Cytokine Handbook
.
1998
Academic Press, San Diego, CA.
15
Wang, J., Q. Lin, H. Langston, M. D. Cooper.
1995
. Resident bone marrow macrophages produce type I interferons that can selectively inhibit interleukin-7 driven growth of B lineage cells.
Immunity
3
:
475
16
Lin, Q., C. Dong, M. D. Cooper.
1998
. Impairment of T and B cell development by treatment with a type I interferon.
J. Exp. Med.
187
:
79
17
Darnell, J. E..
1997
. Stats and gene regulation.
Science
277
:
1630
18
Pellegrini, S., I. Dusanter-Fourt.
1997
. The structure, regulation and function of the Janus kinases (Jaks) and the signal transducers and activators of transcription (Stats).
Eur. J. Biochem.
248
:
615
19
Liu, K. D., S. L. Gaffen, M. A. Goldsmith.
1998
. Jak/Stat signaling by cytokine receptors.
Curr. Opin Immunol.
10
:
271
20
Haque, S. J., B. R. G. Williams.
1998
. Signal transduction in the interferon signal.
Semin. Oncol.
25
:
14
21
Foxwell, B. M., C. Beadling, D. Guschin, I. Kerr, D. Cantrell.
1995
. Interleukin-7 can induce the activation of Jak 1, Jak 3 and STAT 5 proteins in murine cells.
Eur. J. Immunol.
25
:
3041
22
Meraz, M. A., J. M. White, K. C. F. Sheehan, E. A. Bach, S. J. Rodig, A. S. Dighe, D. H. Kaplan, J. K. Riley, A. C. Greenlund, D. Campbell, et al
1996
. Targeted disruption of the Stat-1 gene in mice reveals unexpected physiologic specificity in the Jak-Stat signaling pathway.
Cell
84
:
431
23
Durbin, J. E., R. Hackenmiller, M. C. Simon, D. E. Levy.
1996
. Targeted disruption of the mouse Stat-1 gene results in compromised innate immunity to viral disease.
Cell
84
:
443
24
Borzillo, G. V., K. Endo, Y. Tsujimoto.
1991
. Bcl-2 confers growth and survival advantage to interleukin 7-dependent early pre-B cells which become factor independent by a multistep process in culture.
Oncogene
7
:
869
25
Spangrude, G. J., D. M. Brooks.
1993
. Mouse strain variability in the expression of the hematopoietic stem cell antigen Ly6A/E by bone marrow cells.
Blood
82
:
3327
26
Khodadoust, M. M., K. D. Khan, E. Park, A. L. M. Bothwell.
1998
. Distinct regulatory mechanisms for interferon-α/β (IFN-α/β) and interferon-γ-mediated induction of Ly-6E gene in B cells.
Blood
92
:
2399
27
Cantley, L. C., K. R. Auger, C. Carpenter, B. Duckworth, A. Graziani, R. Kapeller, S. Soltoff.
1991
. Oncogenes and signal transduction.
Cell
64
:
281
28
Pfeffer, L. M., J. E. Mullersman, S. R. Pfeffer, A. Murti, W. Shi, C. H. Yang.
1997
. Stat3 as an adapter to couple phosphatidylinositol 3-kinase to the IFNAR1 chain of the type I interferon receptor.
Science
276
:
1418
29
Uddin, S., E. N. Fish, D. A. Sher, C. Gardziola, M. F. White, L. C. Platanias.
1997
. Activation of the phosphatidylinositol 3-kinase serine kinase by IFN-α.
J. Immunol.
158
:
2390
30
Vlahos, C. J., W. F., K.Y. Hui Matter, R. F. Brown.
1994
. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).
J. Biol. Chem.
18
:
5241
31
Bromberg, J. F., C. M. Horvarth, Z. Wen, R. D. Schreiber, J. E. Darnell, Jr.
1996
. Transcriptionally active Stat-1 is required for the antiproliferative effects of both interferon α and interferon γ.
Proc. Natl. Acad. Sci. USA
93
:
7637
32
Qureshi, S. A., M. Salditt-Georgieff, J. E. Darnell.
1995
. Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3.
Proc. Natl. Acad. Sci. USA
92
:
3829
33
Takeda, K., K. Noguchi, W. Shi, T. Tanaka, M. Matsumoto, N. Yoshida, T. Kishimoto, S. Akira.
1997
. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.
Proc. Natl. Acad. Sci. USA
94
:
3801
34
Yang, C. H., Murti A, L. M. Pfeffer.
1998
. Stat3 complements defects in an interferon-resistant cell line: evidence for an essential role for Stat3 in interferon signaling and biological activities.
Proc. Natl. Acad. Sci. USA
95
:
5568
35
Fruman, D. A., S. B. Snapper, C. M. Yballe, L. Davidson, J. Y. Yu, F. W. Alt, L. C. Cantley.
1999
. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α.
Nature
283
:
393
36
Suzuki, H., Y. Terauchi, M. Fujiwara, S. Aizawa, Y. Yazaki, T. Kadowaki, S. Koyasu.
1999
. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase.
Nature
283
:
390
37
Ramana, C. V., N. Grammatikakis, M. Chernov, H. Nguyen, K. C. Goh, B. R. Williams, and G. R. Stark. Regulation of c-myc expression by IFN-γ trough Stat-1 dependent and -independent pathways. EMBO J.19:263.
38
Kincade, P. W..
1994
. B lymphopoiesis: global factors, local control.
Proc. Natl. Acad. Sci. USA
91
:
2888
39
Vasconcellos, R., D. Braun, A. Coutinho, J. Demengeot.
1999
. Type I IFN sets the stringency of B cell repertoire selection in the bone marrow.
Int. Immunol.
11
:
279
40
Arora, T., G. Floyd-Smith, M. J. Espy, D. F. Jelinek.
1999
. Dissociation between IFN-α induced anti-viral and growth signaling pathways.
J. Immunol.
162
:
3289