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Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking interferon regulatory factor-1.

Tada Y, Ho A, Matsuyama T, Mak TW - J. Exp. Med. (1997)

Bottom Line: Interferon regulatory factor-1 (IRF-1) is a transcription factor that regulates interferon-induced genes and type I interferons.Expression of iNOS was also detected in inflamed spinal cords.These results suggest that IRF-I plays a key role in promoting inflammation and autoimmunity in CIA and EAE animal models.

View Article: PubMed Central - PubMed

Affiliation: Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.

ABSTRACT
Interferon regulatory factor-1 (IRF-1) is a transcription factor that regulates interferon-induced genes and type I interferons. Recently, studies of IRF-l-deficient mice have revealed that IRF-I regulates the induction of molecules that play important roles in inflammation, such as inducible nitric oxide synthase (iNOS) and interleukin-l beta-converting enzyme (ICE). To study the role of IRF-1 in autoimmunity, we investigated type II collagen-induced arthritis (CIA), and experimental allergic encephalomyelitis (EAE), in mice lacking IRF-1. The incidence and severity of CIA were significantly decreased in IRF-1-/- mice compared with IRF-l +/- mice, as was the production of interferon (IFN)-gamma in lymph node cells. Both IRF-l+/- and IRF-1-/- mice exhibited mild and transient disease after adoptive transfer of a type II collagen (CII)-specific T cell line together with sera from arthritic mice, but the IRF-1-/- mice were less severely affected than the IRF-1+/- mice. In addition, the incidence of EAE in IRF-1-/- mice was decreased as compared with IRF-1 +/- mice. Reverse transcription polymerase chain reaction showed that IRF-1 mRNA was constitutively expressed in the spinal cords of IRF-1+/- mice, and was upregulated in mice with clinical EAE. Expression of iNOS was also detected in inflamed spinal cords. These results suggest that IRF-I plays a key role in promoting inflammation and autoimmunity in CIA and EAE animal models.

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Development of CIA in IRF-1+/− and IRF-1−/− DBA/1  mice. IRF-1+/− (squares, n = 23) and IRF-1−/− (circles, n = 29) mice  were immunized with bovine CII and signs of arthritis were monitored as  described in Materials and Methods. A summary of four experiments is  shown. (A) Incidence of arthritis in IRF-1−/− mice was decreased as  compared with that of control IRF-1+/− mice (P <0.005). (B) Arthritis  index, calculated from arthritic mice only, was also decreased in IRF-1−/−  mice after day 42 (P <0.05). Mean arthritis index ± SEM is shown.
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Figure 1: Development of CIA in IRF-1+/− and IRF-1−/− DBA/1 mice. IRF-1+/− (squares, n = 23) and IRF-1−/− (circles, n = 29) mice were immunized with bovine CII and signs of arthritis were monitored as described in Materials and Methods. A summary of four experiments is shown. (A) Incidence of arthritis in IRF-1−/− mice was decreased as compared with that of control IRF-1+/− mice (P <0.005). (B) Arthritis index, calculated from arthritic mice only, was also decreased in IRF-1−/− mice after day 42 (P <0.05). Mean arthritis index ± SEM is shown.

Mentions: IRF-1−/− and IRF-1+/− littermates were immunized with CII and observed for signs of arthritis for up to 10 wk after immunization. Disease incidence and the maximal arthritis index were assessed at the end of this period. The incidence of arthritis calculated from four independent experiments is shown in Fig. 1 A. As shown in Table 1, the incidence in IRF-1−/− mice (37.9%, 11 out of 29 mice) was significantly decreased as compared with IRF-1+/− mice (82.6%, 19 out of 23 mice; P <0.005). There was also a delay in the development of disease in IRF-1−/− mice, because the median day of onset among diseased individuals was day 34 in IRF-1+/− mice, and day 44 in IRF-1−/− mice. Furthermore, the arthritis index (calculated only from arthritic mice) was significantly decreased in IRF-1−/− mice (2.7 ± 0.6) compared with IRF-1+/− mice (6.9 ± 0.7; P <0.01) throughout the course of disease (Fig. 1 B). Histological examination of the phalangeal joints of toes of 4 out of 5 IFR-1+/− mice showed typical arthritis, characterized by dense cellular infiltration and bone erosion (Fig. 2 A). In contrast, most joints of IRF-1−/− mice (6 out of 7 mice) showed either mild infiltration of cells or no sign of inflammation (Fig. 2 B). These data imply that the incidence and the severity of CIA is decreased in IRF-1−/− mice; however, there was no difference in anti-CII IgG antibody level between the two groups of mice at 5 wk after immunization (IRF-1+/−, 60 ± 10 U; IRF-1−/−, 52 ± 12 U).


Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking interferon regulatory factor-1.

Tada Y, Ho A, Matsuyama T, Mak TW - J. Exp. Med. (1997)

Development of CIA in IRF-1+/− and IRF-1−/− DBA/1  mice. IRF-1+/− (squares, n = 23) and IRF-1−/− (circles, n = 29) mice  were immunized with bovine CII and signs of arthritis were monitored as  described in Materials and Methods. A summary of four experiments is  shown. (A) Incidence of arthritis in IRF-1−/− mice was decreased as  compared with that of control IRF-1+/− mice (P <0.005). (B) Arthritis  index, calculated from arthritic mice only, was also decreased in IRF-1−/−  mice after day 42 (P <0.05). Mean arthritis index ± SEM is shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196116&req=5

Figure 1: Development of CIA in IRF-1+/− and IRF-1−/− DBA/1 mice. IRF-1+/− (squares, n = 23) and IRF-1−/− (circles, n = 29) mice were immunized with bovine CII and signs of arthritis were monitored as described in Materials and Methods. A summary of four experiments is shown. (A) Incidence of arthritis in IRF-1−/− mice was decreased as compared with that of control IRF-1+/− mice (P <0.005). (B) Arthritis index, calculated from arthritic mice only, was also decreased in IRF-1−/− mice after day 42 (P <0.05). Mean arthritis index ± SEM is shown.
Mentions: IRF-1−/− and IRF-1+/− littermates were immunized with CII and observed for signs of arthritis for up to 10 wk after immunization. Disease incidence and the maximal arthritis index were assessed at the end of this period. The incidence of arthritis calculated from four independent experiments is shown in Fig. 1 A. As shown in Table 1, the incidence in IRF-1−/− mice (37.9%, 11 out of 29 mice) was significantly decreased as compared with IRF-1+/− mice (82.6%, 19 out of 23 mice; P <0.005). There was also a delay in the development of disease in IRF-1−/− mice, because the median day of onset among diseased individuals was day 34 in IRF-1+/− mice, and day 44 in IRF-1−/− mice. Furthermore, the arthritis index (calculated only from arthritic mice) was significantly decreased in IRF-1−/− mice (2.7 ± 0.6) compared with IRF-1+/− mice (6.9 ± 0.7; P <0.01) throughout the course of disease (Fig. 1 B). Histological examination of the phalangeal joints of toes of 4 out of 5 IFR-1+/− mice showed typical arthritis, characterized by dense cellular infiltration and bone erosion (Fig. 2 A). In contrast, most joints of IRF-1−/− mice (6 out of 7 mice) showed either mild infiltration of cells or no sign of inflammation (Fig. 2 B). These data imply that the incidence and the severity of CIA is decreased in IRF-1−/− mice; however, there was no difference in anti-CII IgG antibody level between the two groups of mice at 5 wk after immunization (IRF-1+/−, 60 ± 10 U; IRF-1−/−, 52 ± 12 U).

Bottom Line: Interferon regulatory factor-1 (IRF-1) is a transcription factor that regulates interferon-induced genes and type I interferons.Expression of iNOS was also detected in inflamed spinal cords.These results suggest that IRF-I plays a key role in promoting inflammation and autoimmunity in CIA and EAE animal models.

View Article: PubMed Central - PubMed

Affiliation: Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.

ABSTRACT
Interferon regulatory factor-1 (IRF-1) is a transcription factor that regulates interferon-induced genes and type I interferons. Recently, studies of IRF-l-deficient mice have revealed that IRF-I regulates the induction of molecules that play important roles in inflammation, such as inducible nitric oxide synthase (iNOS) and interleukin-l beta-converting enzyme (ICE). To study the role of IRF-1 in autoimmunity, we investigated type II collagen-induced arthritis (CIA), and experimental allergic encephalomyelitis (EAE), in mice lacking IRF-1. The incidence and severity of CIA were significantly decreased in IRF-1-/- mice compared with IRF-l +/- mice, as was the production of interferon (IFN)-gamma in lymph node cells. Both IRF-l+/- and IRF-1-/- mice exhibited mild and transient disease after adoptive transfer of a type II collagen (CII)-specific T cell line together with sera from arthritic mice, but the IRF-1-/- mice were less severely affected than the IRF-1+/- mice. In addition, the incidence of EAE in IRF-1-/- mice was decreased as compared with IRF-1 +/- mice. Reverse transcription polymerase chain reaction showed that IRF-1 mRNA was constitutively expressed in the spinal cords of IRF-1+/- mice, and was upregulated in mice with clinical EAE. Expression of iNOS was also detected in inflamed spinal cords. These results suggest that IRF-I plays a key role in promoting inflammation and autoimmunity in CIA and EAE animal models.

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Related in: MedlinePlus