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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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Adoptive transfer of arthritis in IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’  DBA/1 mice. A CII-reactive cell line together with sera from arthritic  mice was injected into naive mice as described in Materials and Methods.  Arthritis index (A), and number of fingers and toes with arthritis (B), were  evaluated. Arthritis index and number of arthritic fingers and toes were  decreased in IRF-1āˆ’/āˆ’ mice (circles) after day 7 (P <0.05 and Pā€‚<0.01, respectively) as compared with those in IRF-1+/āˆ’ mice (squares). In this experiment, all IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’ mice developed arthritis. A representative result from a total of three experiments is shown.
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Figure 4: Adoptive transfer of arthritis in IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’ DBA/1 mice. A CII-reactive cell line together with sera from arthritic mice was injected into naive mice as described in Materials and Methods. Arthritis index (A), and number of fingers and toes with arthritis (B), were evaluated. Arthritis index and number of arthritic fingers and toes were decreased in IRF-1āˆ’/āˆ’ mice (circles) after day 7 (P <0.05 and Pā€‚<0.01, respectively) as compared with those in IRF-1+/āˆ’ mice (squares). In this experiment, all IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’ mice developed arthritis. A representative result from a total of three experiments is shown.

Mentions: Because IRF-1 appeared to be involved in both the induction and the the effector phases of CIA, the effector phase of CIA in IRF-1āˆ’/āˆ’ mice was examined by adoptive transfer. Adoptive transfer of disease has been used in the EAE model and in nonobese diabetes (NOD) mice, but there is no established regimen for CIA. We evaluated a method for adoptive transfer of CIA in which a CII-specific T cell line (established as described in Materials and Methods), together with sera from arthritic mice, is injected into naive DBA/1 mice. The helper T cells and antiCII antibodies required for the initiation of arthritis are injected, while the macrophages and other effector cells are derived from the recipient. Recipient mice developed mild and transient arthritis, which was generally grade 1 in severity (per paw). After day 10ā€“14, these mice either developed stable arthritis, or underwent remission. As shown in Fig. 4 A, the arthritis index in IRF-1āˆ’/āˆ’ mice decreased as compared with that in control IRF-1+/āˆ’ mice after day 7. The number of arthritic fingers and toes was also lower, confirming the decreased severity of disease in IRF-1āˆ’/āˆ’ mice (Fig. 4 B). These results suggest that IRF-1āˆ’/āˆ’ mice develop less severe arthritis than their IRF-1+/āˆ’ counterparts, even in the presence of equal numbers of CII-specific T cells and anti-CII antibodies.


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)

Adoptive transfer of arthritis in IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’  DBA/1 mice. A CII-reactive cell line together with sera from arthritic  mice was injected into naive mice as described in Materials and Methods.  Arthritis index (A), and number of fingers and toes with arthritis (B), were  evaluated. Arthritis index and number of arthritic fingers and toes were  decreased in IRF-1āˆ’/āˆ’ mice (circles) after day 7 (P <0.05 and Pā€‚<0.01, respectively) as compared with those in IRF-1+/āˆ’ mice (squares). In this experiment, all IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’ mice developed arthritis. A representative result from a total of three experiments is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196116&req=5

Figure 4: Adoptive transfer of arthritis in IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’ DBA/1 mice. A CII-reactive cell line together with sera from arthritic mice was injected into naive mice as described in Materials and Methods. Arthritis index (A), and number of fingers and toes with arthritis (B), were evaluated. Arthritis index and number of arthritic fingers and toes were decreased in IRF-1āˆ’/āˆ’ mice (circles) after day 7 (P <0.05 and Pā€‚<0.01, respectively) as compared with those in IRF-1+/āˆ’ mice (squares). In this experiment, all IRF-1+/āˆ’ and IRF-1āˆ’/āˆ’ mice developed arthritis. A representative result from a total of three experiments is shown.
Mentions: Because IRF-1 appeared to be involved in both the induction and the the effector phases of CIA, the effector phase of CIA in IRF-1āˆ’/āˆ’ mice was examined by adoptive transfer. Adoptive transfer of disease has been used in the EAE model and in nonobese diabetes (NOD) mice, but there is no established regimen for CIA. We evaluated a method for adoptive transfer of CIA in which a CII-specific T cell line (established as described in Materials and Methods), together with sera from arthritic mice, is injected into naive DBA/1 mice. The helper T cells and antiCII antibodies required for the initiation of arthritis are injected, while the macrophages and other effector cells are derived from the recipient. Recipient mice developed mild and transient arthritis, which was generally grade 1 in severity (per paw). After day 10ā€“14, these mice either developed stable arthritis, or underwent remission. As shown in Fig. 4 A, the arthritis index in IRF-1āˆ’/āˆ’ mice decreased as compared with that in control IRF-1+/āˆ’ mice after day 7. The number of arthritic fingers and toes was also lower, confirming the decreased severity of disease in IRF-1āˆ’/āˆ’ mice (Fig. 4 B). These results suggest that IRF-1āˆ’/āˆ’ mice develop less severe arthritis than their IRF-1+/āˆ’ counterparts, even in the presence of equal numbers of CII-specific T cells and anti-CII antibodies.

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.

Show MeSH
Related in: MedlinePlus