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Regulatory aspects of innate immune responses
Örebro University, School of Science and Technology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Activation of innate immunity is regulated by a variety of signaling molecules within the immune cells. The present thesis was aimed to improve our understanding of innate signaling mechanism and their possible use as bio-indicators of exposure and disease. The first part of the thesis deals with the involvement of TOM1L1 (Target of Myb1 like 1) in innate immune signaling and regulation of inflammatory cytokines in immune cells (study I and II). The initial event of T-cells activation depend on the recruitment of Src family kinases Fyn and Lck, leading to interleukine-2 (IL-2) production in T cells. Understanding the regulatory aspects of IL-2 induction in T-cells is of importance as IL-2 is a key regulator for T-cell proliferation and survival. Interaction screening indicated the ability of TOM1L1 protein to interact with Fyn, and Lck, that is important for IL-2 production in Jurkat T-cells. TOM1L1 silencing decreased the levels of CD3/CD28 dependent induction of IL-2 in Jurkat T-cells, and LPS dependent induction of TNF-α in THP-1. Furthermore, overexpression of TOM1L1 in Jurkat T-cells causes an increase of STAT3 expression. This was accompanied by an increase in the levels of IL-1β dependent induction of IL-6 and TNF-α in THP-1 cells. These results indicate that TOM1L11 participate in regulation of innate immune response. The second part of the thesis deals with development of innate immune signaling responses used as a diagnosis tools for disease and exposure (study III and IV). Inflammatory diseases are associated with innate immune reactions. In response to inflammation, the immune cells release inflammatory cytokines such as IL-1-β, IL-2, IL-6, IL-10, TNF-α and CXCL8. These cytokines are regulated by stress related kinases include MAP kinase proteins such as ERK1-2, JNK, and MAPK p38, through activation of transcription factors AP-1, ATF-2, and NF-AT. In a clinical study, it was observed that activated MAPK p38 has a potential role in the regulation of IL-10 expression in intermittent claudication. However, expression of IL-10 and MAPK p38 was opposed in stable angina group. Therefore, targeting MAPK p38 in inflammatory disease such as cardiovascular diseases, diabetes, and rheumatoid arthritis might be useful in development of treatment strategies. Innate immune reactions can also be used to monitor stress related inflammatory responses following environmental exposure of immune cells. Inflammatory responses of exposure were studied by in vitro exposure to waters from sewage treatment works and recipient waters. The analysis shows that exposure to inland waters can result in activated immune responses and that these responses are both site dependent and vary over time.

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2011. , p. 56
Series
Örebro Studies in Life Science ; 9
Keywords [en]
Innate immunity, TOM1L1, inflammatory responses
National Category
Natural Sciences Biological Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-21384ISBN: 978-91-7668-816-8 (print)OAI: oai:DiVA.org:oru-21384DiVA, id: diva2:484979
Public defence
2011-10-31, Musikhögskolan, hörsal M, Fakultetsgatan 1, Örebro, 10:00 (English)
Opponent
Supervisors
Available from: 2012-01-30 Created: 2012-01-27 Last updated: 2017-10-17Bibliographically approved
List of papers
1. TOM1L is involved in a novel signaling pathway important for the IL-2 production in Jurkat T cells stimulated by CD3/CD28 CoLigation
Open this publication in new window or tab >>TOM1L is involved in a novel signaling pathway important for the IL-2 production in Jurkat T cells stimulated by CD3/CD28 CoLigation
2009 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, p. 416298-Article in journal (Refereed) Published
Abstract [en]

TOM1L (target of Myb-1 Like) was identified as a binding partner for the full length and catalytically-active Lck in a yeast 2-hybrid screening assay. Here we show that in Jurkat T cells stimulated by CD3/CD28 coligation where the expression of TOM1L is reduced by lenti virus mediated-siRNA results in a dramatically lower IL-2 production. The production of IL-2 in siRNA treated cells stimulated with PMA/ionomycin was not affected indicating an involvement of TOM1L in a pathway proximal of TCR and CD28. The coexpression of Fyn with TOM1L increased the level of the phosphorylated form of Fyn indicating that TOM1L has the ability to activate Fyn. The ability of TOM1L to activate Fyn was further shown in a kinase assay using angiotensin II as a substrate. By confocal microscopy, we show that the expression of TOM1L in non-treated HeLa and SK-N-SH cells colocalizes with the mitochondrial membrane but not with lysosomal compartments or the trans-Golgi network. Furthermore, we show that the over-expression of TOM1L in Jurkat cells causes an increase of the STAT3 expression. Based on our results, we here propose that TOM1L is involved in a novel signaling pathway that is important for the IL-2 production in T cells. Copyright (C) 2009 Ahmed Elmarghani et al.

Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2009
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-21385 (URN)10.1155/2009/416298 (DOI)000276144100001 ()2-s2.0-77949305423 (Scopus ID)
Available from: 2012-01-27 Created: 2012-01-27 Last updated: 2017-12-08Bibliographically approved
2. Involvement of TOM1L1 in cytokine regulation in THP-1 cells
Open this publication in new window or tab >>Involvement of TOM1L1 in cytokine regulation in THP-1 cells
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-21459 (URN)
Available from: 2012-02-02 Created: 2012-02-02 Last updated: 2017-10-17Bibliographically approved
3. High MAPK p38 activity and low level of IL-10 in intermittent claudication as opposed to stable angina
Open this publication in new window or tab >>High MAPK p38 activity and low level of IL-10 in intermittent claudication as opposed to stable angina
Show others...
2010 (English)In: International Journal of Angiology, ISSN 0392-9590, E-ISSN 1827-1839, Vol. 29, no 4, p. 331-337Article in journal (Refereed) Published
Abstract [en]

AIM:

The aim of the present pilot study was to relate the activity of MAPK p38 with the levels of pro- and anti-inflammatory cytokines in a small cohort of patients with either stable angina (N=5) or intermittent claudication (N=5) compared to healthy controls (N=10).

METHODS:

The activity of MAPK p38 was determined in peripheral blood mononuclear cells, isolated from whole blood by western blot using phospho-specific anti-MAPK p38 antibodies. Cytokine levels of 11 pro- and anti-inflammatory cytokines were determined from the serum using flow cytometry.

RESULTS:

We found a significant elevation of the MAPK p38 activity in the intermittent claudication group (P=0.0027) compared with the healthy control group whereas the stable angina group showed similar MAPK p38 activity as the healthy control group. The IL-10 level in serum found in the stable angina group was significantly higher compared with both the healthy control group (P=0.0116) and the intermittent claudication group (P=0.0317).

CONCLUSION:

Our results imply that there is a casual relationship between increased levels of the anti-inflammatory cytokines IL-10 and IL-4 and the activity of the MAPK p38. Possibly has IL-10 a protective role that down-regulates the activity of MAPK p38 and thereby further inflammatory processes in stable angina patients.

Place, publisher, year, edition, pages
Torino: Minerva Medica, 2010
Keywords
p38 mitogen-activated protein kinases, Interleukin-10, Intermittent claudication
National Category
Medical and Health Sciences Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:oru:diva-12845 (URN)000283516700007 ()20671651 (PubMedID)
Available from: 2011-01-10 Created: 2011-01-03 Last updated: 2017-12-11Bibliographically approved
4. Immune cell activation by sewage treatment plant effluents and inland waters in Sweden
Open this publication in new window or tab >>Immune cell activation by sewage treatment plant effluents and inland waters in Sweden
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Biology
Identifiers
urn:nbn:se:oru:diva-21457 (URN)
Available from: 2012-02-02 Created: 2012-02-02 Last updated: 2017-10-17Bibliographically approved

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