Identification of cellular targets in regulating inflammatory pathways

Amna Al-Araimi, Fahad AL Zadjali

Research output: ThesisDoctoral Thesis


Inflammation plays a central role in many of the chronic diseases including type 2 diabetes, obesity, autoimmune and inflammatory bowel diseases as well as cancer. Detailed investigation of inflammatory pathways in both molecular and cellular levels is imperative for understanding the disease process and progression. Exploration of new therapeutic approaches has now become mandatory.

Recent studies demonstrated that inflammatory pathways might be regulated by the cellular actions of SOCS2 protein. In contrast to the available evidence focusing on SOCS2 anti-inflammatory effects, the cellular target remain largely unexplored. This thesis will undertake a multi- faceted approach to evaluate the physiological function of SOCS2 protein through identifying its substrate and enhancing growth hormone sensitivity in an acute inflammation model of colitis.

The first part of the study was carried out to identify new molecular targets of SOCS2 using quantitative proteomic approach. We found the serine-threonine kinase NDR1, a known regulator of TNFα-NF-κB signaling, as a novel target of SOCS2 protein. In addition, we investigated the functional interplay between SOCS2 and NDR1, which would provide more understanding of SOCS2 function and how its deregulation causes immune-pathological conditions. We showed that SOCS2 interacts with NDR1 and favors its degradation through ubiquitin-mediated proteolysis. Our data provided evidence to suggest that SOCS2 restriction of the TNFα-NF-κB pathway is mediated, at least partially, through NDR1. In line with our findings, we used a SOCS2-/- mice model of colon inflammation, which strengthen the view that SOCS2-deficiency is hyper-inflammatory and showed a negative relationship between SOCS2 with NDR1 and nuclear p65.

The second part consists of a GH-SOCS2 axis molecular analysis in the inflammatory process of an in vivo model using DSS-induced colitis. We demonstrated that the deletion of SOCS2 induced inflammatory process as reported earlier in steatohepatitis model and this may contribute to higher disease activity. Despite the acute inflammation, our finding of increased growth hormone sensitivity by SOCS2 deletion showed less tissue damage and less fibrotic lesions, which is explained by lower α-SMA expression and less collagen deposition in the recovery phase. In addition, enhanced GH sensitivity via SOCS2 deletion showed higher intestinal epithelial regeneration through BrdU proliferation assay. Furthermore, both expression of TGF-β and TGF-β receptors were down regulated in SOCS2 knockout mice.

Another important consideration in my thesis is that we investigated other modalities to manage the inflammatory processes. Gum Arabic (GA) is an herbal medicine, which acts as an anti-oxidant compound and we suggest it has a beneficial effects on ulcerative colitis disease. To substantiate this assumption, macroscopic and microscopic parameters analysis was carried out to evaluate the protective effect of GA in improving the severity of the UC disease through DSS-induced colitis in vivo model. Our data indicated that GA effectively facilitated recovery of pathologic changes in the colon, as evidenced by a significant less body weight reduction, decrease of disease activity index and histopathological score. Additionally, we found that intake of GA continuously provide higher intestinal epithelial regeneration as well as less fibrotic markers that indicate a major role of GA in fibroblast function regulation.

These findings provide novel insights into E3 ligase activity of SOCS2 and point towards an explanation for the effects of SOCS2 on NF-κB activity. Moreover, a new mechanistic understanding of SOCS2 role with interaction of GH in disease activity of inflammatory bowl disease has investigated. In addition, administration of GA was found to have protective and alleviative effect on the severity of DSS-induced colitis model. Our knowledge of such mechanisms is valuable as to optimize and design new strategies to enhance regeneration of damaged intestinal epithelial cells. Further understanding of these mechanisms could eventually lead to elucidation of new targets for interventions that may modulate disease incidence or activity.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Sultan Qaboos University
  • AL Zadjali, Fahad, Supervisor
  • Koh, Crystal, Advisor
  • Al-Hashmi, Sulaiman, Advisor, External person
Award dateAug 28 2017
Publication statusPublished - 2017

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