- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- UBC Theses and Dissertations /
- Biological and biochemical analyses of the distinctive...
Open Collections
UBC Theses and Dissertations
UBC Theses and Dissertations
Biological and biochemical analyses of the distinctive intracellular signals activated by interleukin-4 Levings, Megan K.
Abstract
Interleukin-4 (IL-4) is a type I cytokine which acts on multiple hemopoietic cells to promote an antibody-mediated response to infection. Dysregulated production or function of IL-4 can exacerbate diseases such as allergy, asthma and rheumatoid arthritis. In order to better understand the biochemical mechanisms by which IL-4 mediates its pleiotropic biological effects, I investigated two distinctive aspects of the intracellular signals activated by IL-4. First, IL-4 is different from most type I cytokines in its inability to activate Ras or Raf-1. IL-4 also fails to support cellular growth. I demonstrated that the signals provided by an active Ras or an inducibly active Raf-1 kinase could synergise with IL-4 to promote cell-cycle progression. Further investigation of the biochemical events associated with the stimulation of long-term growth showed that active Raf-1 not only synergised with IL-4 to stimulate growth, but also to increase levels of c-jun N-terminal kinase (JNK) activity. These observations raise the possibility that Raf-1 may be involved in regulating JNK activity, and that JNK may be involved in mediating certain effects of IL-4. Second, IL-4 and IL-13 are the only cytokines that activate the transcription factor STAT-6. I determined that activation of STAT-6 was required for IL-4- stimulated cell survival. However, I found evidence that this requirement for STAT-6 was indirect, and possibly related to STAT-6-dependent, IL-4-stimulated expression of the IL-4 receptor. I next investigated the hypothesis that STAT-6 was required for IL-4-mediated suppression of tumor necrosis factor α (TNFα) and interleukin-12 (IL-12) production in macrophages. When STAT-6 null macrophages were stimulated with lipopolysaccharide (LPS) and interferon γ (IFNγ), I continued to observe a significant inhibition of TNFα and IL-12 by IL- 4, suggesting that IL-4 activates distinct, STAT-6 independent, inhibitory paths. IFNγ antagonizes many of the effects of IL-4, and I determined that IFNγ may regulate the activity of STAT6 by altering expression of a STAT6 inhibitor, Bcl-6. Further investigation into the roles of JNK, Bcl-6 and novel, non-STAT-6-dependent pathways will be important for the design of strategies to therapeutically modulate the intracellular signals activated by IL-4.
Item Metadata
Title |
Biological and biochemical analyses of the distinctive intracellular signals activated by interleukin-4
|
Creator | |
Publisher |
University of British Columbia
|
Date Issued |
1998
|
Description |
Interleukin-4 (IL-4) is a type I cytokine which acts on multiple hemopoietic cells to promote an
antibody-mediated response to infection. Dysregulated production or function of IL-4 can
exacerbate diseases such as allergy, asthma and rheumatoid arthritis. In order to better
understand the biochemical mechanisms by which IL-4 mediates its pleiotropic biological
effects, I investigated two distinctive aspects of the intracellular signals activated by IL-4. First,
IL-4 is different from most type I cytokines in its inability to activate Ras or Raf-1. IL-4 also
fails to support cellular growth. I demonstrated that the signals provided by an active Ras or an
inducibly active Raf-1 kinase could synergise with IL-4 to promote cell-cycle progression.
Further investigation of the biochemical events associated with the stimulation of long-term
growth showed that active Raf-1 not only synergised with IL-4 to stimulate growth, but also to
increase levels of c-jun N-terminal kinase (JNK) activity. These observations raise the
possibility that Raf-1 may be involved in regulating JNK activity, and that JNK may be involved
in mediating certain effects of IL-4. Second, IL-4 and IL-13 are the only cytokines that activate
the transcription factor STAT-6. I determined that activation of STAT-6 was required for IL-4-
stimulated cell survival. However, I found evidence that this requirement for STAT-6 was
indirect, and possibly related to STAT-6-dependent, IL-4-stimulated expression of the IL-4
receptor. I next investigated the hypothesis that STAT-6 was required for IL-4-mediated
suppression of tumor necrosis factor α (TNFα) and interleukin-12 (IL-12) production in
macrophages. When STAT-6 null macrophages were stimulated with lipopolysaccharide (LPS)
and interferon γ (IFNγ), I continued to observe a significant inhibition of TNFα and IL-12 by IL-
4, suggesting that IL-4 activates distinct, STAT-6 independent, inhibitory paths. IFNγ
antagonizes many of the effects of IL-4, and I determined that IFNγ may regulate the activity of
STAT6 by altering expression of a STAT6 inhibitor, Bcl-6. Further investigation into the roles
of JNK, Bcl-6 and novel, non-STAT-6-dependent pathways will be important for the design of
strategies to therapeutically modulate the intracellular signals activated by IL-4.
|
Extent |
7918535 bytes
|
Genre | |
Type | |
File Format |
application/pdf
|
Language |
eng
|
Date Available |
2009-07-03
|
Provider |
Vancouver : University of British Columbia Library
|
Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
|
DOI |
10.14288/1.0089320
|
URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
|
Graduation Date |
1999-05
|
Campus | |
Scholarly Level |
Graduate
|
Aggregated Source Repository |
DSpace
|
Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.