S-Space College of Veterinary Medicine (수의과대학) Dept. of Veterinary Medicine (수의학과) Theses (Ph.D. / Sc.D._수의학과)
The Role of TRIF and RIP2 and Inhibitory effect of Mycobacterium tuberculosis derived Heat shock protein 70 on Development of Allergic Airway Inflammation
알러지성 기도 염증 발생에서 TRIF과 RIP2의 역할 및 결핵균 유래 열충격 단백질70의 억제효과
- 수의과대학 수의학과
- Issue Date
- 서울대학교 대학원
- Pattern recognition receptors; Toll-like receptors; Nod-like receptors; Mycobacterium tuberculosis; Heat shock protein 70; Dendritic cells; Allergic airway inflammation
- 학위논문 (박사)-- 서울대학교 대학원 : 수의학과, 2015. 2. 박재학.
- Allergic asthma is the chronic lung disease influencing over 300 million people of all ages and characterized by airway hyperreactivity and mucous oversecretion induce the intermittent airway obstruction. Medication to control the phenotypes of allergic asthma has been major strategies for asthma treatment. However, they are not complete cure for allergic asthma.
Pattern recognition receptors (PRRs) are component of innate immunity and initiate the immune response by recognizing the microorganism-derived materials. Previous studies reported that PRRs are related to the development of allergic asthma and there have been many report to evalulate the therapeutic functions of toll-like receptors (TLR) ligand in allergic asthma. These are suggesting that studying about the role of PRRs signaling in allergic asthma and finding effective materials are necessary for asthma treatment.
In this research, to determine the role of PRRs signaling in allergic asthma, allergic airway inflammation mice model was used. And the effect of Mycobacterium tuberculosis derived heat shock protein 70 (Mtb Hsp70) which is potent immune modulator and ligand of Toll-like receptor was evaulated using allergic airway inflammation mice model. In addition, bone marrow-derived dendritic cells were used for studying the role of TLR in activation of dendritic cells by Mtb Hsp70.
In chapter I, the role of TRIF, adaptor molecule of TLR3 and TLR4 signaling, in the development of allergic airway inflammation were studied. I confirmed the increased airway inflammation and Th2 immune response in OVA treated mice. However, histopathological assessment, cytokine analysis, cellular analysis in bronchoalveolar fluid, and serum immunoglobulin analysis revealed that the severity of inflammation in airway inflammation in TRIF-deficient mice was comparable to that in WT mice.
In chapter II, the role of RIP2, adaptor molecule of Nod1 and Nod2 signaling, in the development of allergic airway inflammation were studied using mice model. Deficiency of RIP2 is not critical to develop allergic airwa inflammation in mice.
In chapter III, the beneficial effect of Mtb Hsp70 on allergic airway inflammation and their molecular mechanism were studied. In allergen induced allergic airway inflammation model, co-administration of purified recombinant Mtb Hsp70 in sensitization phase reduced indicaotors associated with allergic inflammation. However, these effects of Mtb Hsp70 were abolished in TLR2 and TLR4-deficient mice. In conclusion, our results revealed the inhibitory effect of Mtb Hsp70 on allergic airway inflammation and TLR2 and TLR4 signaling involed in these effects.
In chapter IV, dendritic cells were used for studying the role of TLR2 and TLR4 signaling in effect of Mtb Hsp70. Both TLR2 and TLR4 were required for activation of dendritic cells by purified recombinant Mtb Hsp70. In addition, TRIF and MyD88 are also requried for activation of dendritic cells by Mtb Hsp70. In chapter V, Nod2 signaling has synergistic effect on immune activation induced by TLRs activation. So, the effect of MDP, a ligand of Nod2, on dendritic cell activation by Mtb Hsp70 was studied. In vitro experiments revealed that MDP enhanced the effect of Mtb Hsp70 on activation of dendritic cells.
In this study, it was observed that TRIF and RIP2 did not have critical role in development of allergic airway inflammation in mice model. And Mtb Hsp70 attenuated the development of allergic airway inflammation and these effects are mediated by TLR2 and TLR4 signaling. Study using dendritic cells showed that TLR2 and TLR4 signaling pathway are related to the effect of Mtb Hsp70 and MDP increased the effects of Mtb Hsp70. I expect this result may help to understand the function of pattern recognition receptors in allergic asthma and develop novel therapeutic agent.