Caging a Beast in the Inflammation Arena: Use of Chinese Medicinal Herbs to Inhibit a Late Mediator of Lethal Sepsis, HMGB1

Abstract

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection, which kills > 225,000 people annually in the U.S. alone. The high mortality of sepsis is partly mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF) and late (e.g., HMGB1) pro-inflammatory cytokines. Although early proinflammatory cytokines may be protective against infection, excessive accumulation of late-acting proinflammatory mediators (such as HMGB1) may sustain a potentially injurious inflammatory response. Agents capable of inhibiting HMGB1 activities (e.g., neutralizing antibodies) or release [e.g., Chinese herbs, Danggui (Angelica sinensis), Danshen (Salvia miltiorrhiza) and Green tea (Camellia sinensis)] rescue mice from lethal sepsis even when given 24 hours after onset of the disease. Here we review emerging evidence that support a critical role for extracellular HMGB1 as a late mediator of lethal sepsis, and several commonly used Chinese herbs (Danggui, Danshen and Green tea) as potential HMGB1- targeting therapeutic agents in experimental sepsis.

Keywords: Chinese herbs; Inate immune cells; catechin; cytokines; sepsis; tanshinone.

Figure 1

Amino acid sequence of human HMGB1. The N-terminal portion of HMGB1 comprises two internal repeats of a positively charged domain of about 80 amino acids (termed “HMG boxes”) (shown by bold text). The cytokine-stimulating motif (“Cytokine Domain”) of HMGB1 does not overlap with its RAGE-binding site, supporting the potential involvement of other cell surface receptors (such as TLR2 and TLR4) for HMGB1- mediated inflammatory responses.

Figure 2

Schematic summary of recent development in pharmacological inhibition of HMGB1 release and action. In addition to HMGBl-specific antibodies, a number of commonly used Chinese herbs (e.g., Danggui (Angelica sinensis), Danshen (Salvia miltiorrhiza) and Green tea (Camellia sinensis)] are capable of inhibiting HMGB1 release or cytokine activities, thereby rescuing animals from lethal experimental sepsis.

Figure 3

HMGBl mediates proinflammatory responses. In vivo, administration of HMGBl via intracerebro-ventricular, intratracheal, intraperitoneal, and intraarticular routes induces marked inflammatory responses. In vitro, HMGBl activate various innate immune cells, and facilitate innate recognition of microbial products (such as CpG-DNA).

Figure 4

Structures of major components of Danshen (A) and Green tea (B). Danshen contains abundant red pigments termed tanshinone I, tanshinone IIA, and cryptotanshinone. Green tea contains catechins which harbor two or more aromatic rings (each carrying at least one aromatic hydroxyl) connected with a carbon bridge (consisting of five carbons and one oxygen).