Modulation of the inflammatory response by triptolide and MAP kinase Phosphatase-1.

摘要

The primary function of the immune system is to prevent disease by detecting and eliminating pathogenic organisms or host's abnormal cells as a result of infection or mutation while avoiding self-destruction. A delicate balance must be achieved between the timely and appropriate activation of the immune system and subsequent deactivation when pathogens abnormal cells are cleared. An adequate production of pro-inflammatory cytokines plays a crucial role in effective host immune defense, and abnormal proinflammatory cytokine production can cause various illnesses. The immune system utilizes a variety of mechanisms to achieve adequate immune responses including balanced cytokine production to combat the diverse and ever changing microorganisms. Feedback control through the induction of either intracellular or secreted regulators is a major mechanism employed by the immune system to fine-tune the host responses. Modulation of the immune response pathways by ingredients of certain plants may account for the therapeutic benefits observed in alternative medicines. This thesis will focus on the regulation of the inflammatory response by two completely different immune modulators: MAP kinase Phosphatase-1, an endogenous protein phosphatase, and triptolide, a small molecule isolated from an anti-rheumatic herb in Chinese medicine, T. wilfordii Hook F. In Chapter 1, we will briefly review our current understanding of the immune response to pathogenic organisms, and introduce the basic signaling pathways as well as the key players involved, including MKP-1. We will also briefly summarize the properties of triptolide, and our understanding of its anti-inflammatory mechanisms. Chapter 2 will include a detailed description of our studies on the therapeutic mechanism of triptolide as an anti-inflammatory agent. In Chapter 3, we will switch to MKP-1, and address the basic mechanism via which MKP-1 regulates the innate immune responses. This chapter will focus on the effects of Mkp-1 knockout on cytokine mRNA stability. In Chapter 4, we will present our work on the role of MKP-1 in the pathogenesis of inflammatory bowel disease, using an IL-10 knockout mouse model. Finally, we will summarize our findings and propose a general model illustrating the modes of action of MKP-1 and triptolide in the modulation of inflammatory responses.