The primary function of the immune system is to detect and eliminate pathogenic organisms and cancer cells. A delicate equilibrium must be achieved between the timely and appropriate activation of the immune system and subsequent deactivation when pathogens or cancer cells are cleared. Adequate production of pro-inflammatory cytokines plays a crucial role in effective host immune defense, and abnormal pro-inflammatory 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 or malignant cells. 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. We examined the effect of two different immune modulators on regulation of the inflammatory response: triptolide, a small molecule isolated from an anti-rheumatic herb in Chinese medicine, T. wilfordii Hook F. and MKP-1, an endogenous protein phosphatase.
Triptolide possesses potent anti-inflammatory and immunosuppressive properties. It inhibits pro-inflammatory cytokine production in macrophages stimulated with TLR ligands at both mRNA and protein levels in a dose-dependent manner. Triptolide also blocks gene transcriptional induction regulated by various transcription factors including NF-kB, VP-16 and HSF-1. Triptolide exerts its activities without inhibiting IkB-alpha phosphorylation, degradation or affecting NF-kB DNA-binding activity.
MKP-1 is a critical negative regulator of p38 and JNK MAP kinases, and plays a pivotal role in the regulation of the inflammatory response. Mkp-1 deficiency enhances the production of pro-inflammatory cytokine and iNOS mRNAs and stabilizes their mRNA transcripts.
To understand the role of MKP-1 in the regulation of mucosal immune responses, we studied the effect of Mkp-1 deletion in an Il-10 knockout mouse model of inflammatory bowel disease (IBD). Mice lacking both Mkp-1 and Il-10 are highly susceptible to the development of colitis as well as conjunctivitis and blepharitis, even in an SPF environment. Innate and adaptive immune effector cells of double knockout mice are skewed towards an exaggerated Th-1 response. Our findings support a pivotal role for MKP-1 in the prevention of IBD, and may have important clinical implications in the field of IBD.