Anti-inflammatory Activity of Gumiganghwaltang through the Inhibition of Nuclear Factor-κB Activation in Peritoneal Macrophages

Abstract

Gumiganghwaltang (GMGHT) consists of 9 different herbs and is a Korean herbal prescription, which has been commonly used to treat a cold and inflammatory diseases in Korea. However, it is still unclear how it regulates the immune or inflammatory responses.Macrophage activation is known to play an important role in the inflammatory process 1,2) and produce potent proinflammatory cytokines such as tumor necrosis factor (TNF)-a, and interleukin (IL)-6 which induce inflammation and recruit other immune cells, e.g., neutrophils and T lymphocytes. 3)Although these proinflammatory cytokines are beneficial to the host defense, they can also trigger pathological conditions when expressed in excess.4) For example, massive stimulation of macrophages after a severe Gram-negative bacterial infection leads to excessive production of proinflammatory cytokines and the development of fatal septic shock syndrome, and multiple organ failure. 4,5) In addition, higher levels of proinflammatory cytokines are also implicated in a variety of chronic inflammatory diseases including rheumatoid arthritis, psoriasis, and Crohn's disease. 4)Nitric oxide (NO) produced by the inducible NO synthase (iNOS) 6) isoform is an essential component of the host innate immune and inflammatory response to a variety of pathogens, such as intracellular bacteria, viruses, fungi, and parasites. 7,8) Nevertheless, as for other components of the host inflammatory and immune response, excessive activation of iNOS results in cardiovascular 9) and organ dysfunction 6) in clinical 10) or experimental situations of inflammatory disease of both septic 11) and nonseptic 12) etiology. Cyclooxygenases (COX) produce various types of prostaglandins (PGs), which are implicated in various physiological events including progression of inflammation, immunomodulation, and transmission of pain.13) Two COX isoenzymes were identified: COX-1, the constitutive enzyme makes PGs that protect the stomach and kidney from damage and COX-2, the inducible enzyme induced by inflammatory stimuli such as cytokines produces PGs that contribute to the pain and swelling of inflammation. 14-16) We examined the effects of GMGHT on lipopolysaccaride (LPS)-induced cytokines (TNF-a and IL-6) production, COX-2, and iNOS protein expression from mouse peritoneal macrophages.Nuclear factor-kappa B (NF-kB) plays a critical role in the expression of many genes involved in immune and inflammatory responses. [17][18][19] In unstimulated cells, Rel protein dimers, mainly p50 and p65 subunits, are sequestered in the cytoplasm in complex with one of the several inhibitors of NF-kB. The activation of NF-kB is the consequence of phosphorylation of two specific serines near the N terminus of Ik B-a and its degradation. The phosphorylation of IkB-a lead to the ubiquitination, resulting in the degradation, which targets the protein for degradation by the 26S proteasome and the translocation of NF-kB to the nucleus. 20)The present study was designed to investigate whether GMGHT could modulate expression of cytokin...

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