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Journal of Chinese Integrative Medicine ›› 2010, Vol. 8 ›› Issue (11): 1060-1069.doi: 10.3736/jcim20101110

• Original Expreimental Research • Previous Articles     Next Articles

Acetyl-11-keto-beta-boswellic acid and arsenic trioxide regulate the productions and activities of matrix metalloproteinases in human skin fibroblasts and human leukemia cell line THP-1

Ya-hui Lianga,b,Ping Lia, Jing-xia Zhaoa, Xin Liua, Qi-fu Huangc   

  1. a Beijing Institute of Chinese Medicine, Beijing Hospital of Chinese Medicine, Capital Medical University, Beijing 100010, China
    b Beijing Rehabilitation Center, Beijing 100144, China
    c School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
  • Received:2010-04-05 Accepted:2010-07-07 Online:2010-11-20 Published:2010-11-15
  • Contact: Ping Li E-mail:liping411@yahoo.com.cn

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Objective

In order to reveal the treatment mechanism of Chinese medicine with the effect of activating blood and resolving putridity, we selected acetyl-11-keto-beta-boswellic acid (AKBA) and arsenic trioxide (ATO), the main monomeric components of frankincense and arsenolite which are two most commonly used Chinese medicine with effect of activating blood and resolving putridity. We combined AKBA and ATO as a compound, and explored its regulatory role in productions and activities of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 in human skin fibroblasts (HSFbs) and human acute monocytic leukemia cell line THP-1 in inflammatory state.

Methods

In order to simulate the inflammatory micro-environment of chronic wounds, we established 3 cell models: HSFb model activated by tumor necrosis factor-alpha (TNF-α), THP-1 cell model activated by phorbol-12-myristate-13-acetate (PMA) and HSFb-THP-1 cell coculture system. AKBA and ATO were cocultured with these cell models. Enzyme-linked immunosorbent assay (ELISA), gelatin zymography assay and reverse transcription-polymerase chain reaction (RT-PCR) were used to test the secretions, activities and mRNA expressions of MMP-1, MMP-2 and MMP-9. In the study of the regulatory mechanism of AKBA and ATO on MMPs, AKBA and ATO were cocultured with the cell models. ELISA was used to test the secretions of TNF-α and interleukin-1beta (IL-β) and Western blot was used to test the phosphorylation levels of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated proteinkinase (p38MAPK).

Results

Compound of AKBA and ATO inhibited MMP-1, MMP-2 and MMP-9 mRNA expressions, secretions and activities respectively in HSFbs and THP-1 cells in inflammatory state (P<0.05, P<0.01). Also compound of AKBA and ATO inhibited secretions of TNF-α and IL-1β in THP-1 cells and cell coculture system (P<0.01). It also decreased the phosphorylation of ERK1/2 and p38 MAPK in HSFbs and THP-1 cells (P<0.05, P<0.01).

Conclusion

The combined use of AKBA and ATO which in line with the rule of activating blood and resolving putridity inhibits fibroblasts and inflammatory cells in producing MMPs in inflammatory state through inhibiting the release of inflammatory factors and MAPK cascade pathway.

Key words: Acetyl-ll-keto-beta-boswellic acid, Arsenic trioxide, Fibroblasts, Monocytes, THP-1, Matrix metalloproteinases

Figure 1

Identification of fibroblasts by immunocytochemical method (Light microscopy, ×200) A: Expression of vimentin in fibroblasts; B: Negative control (anti-vimentin antibody was replaced by PBS)."

Table 1

Cytotoxicity of AKBA to HSFb and THP-1 cells"

Table 2

Cytotoxicity of ATO to HSFb and THP-1 cells"

Table 3

Cytotoxicity of AKBA and ATO combination to HSFb and THP-1 cells"

Table 4

Effects of AKBA and ATO on secretion of MMP-1, MMP-2 and MMP-9 by HSFb and THP-1 cells"

Figure 2

Effects of AKBA and ATO combination on expression of MMP-1 mRNA in HSFb 1: Control group; 2: TNF-α group; 3: TNF-α+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. △P<0.05, △△P<0.01, vs TNF-α group"

Figure 3

Effects of AKBA and ATO combination on expression of MMP-2 mRNA in HSFb1: Control group; 2: TNF-α group; 3: TNF-α+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. △P<0.05, △△P<0.01, vs TNF-α group."

Figure 4

Effects of AKBA and ATO combination on expression of MMP-9 mRNA in THP-1 cells1: Control group; 2: PMA group; 3: PMA+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. ▲▲P<0.01, vs PMA group."

Figure 5

Effects of AKBA and ATO combination on MMP-2 activity in culture supernatants of HSFb1: Control group; 2: TNF-α group; 3: TNF-α+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. △P<0.05, △△P<0.01, vs TNF-α group."

Figure 6

Effects of AKBA and ATO combination on MMP-9 activity in culture supernatants of THP-1 cells1: Control group; 2: PMA group; 3: PMA+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. ▲▲P<0.01, vs PMA group."

Figure 7

Effects of AKBA and ATO on MMP-2 and MMP-9 activities in supernatants of cell coculture system1: Control group; 2: PMA group; 3: PMA+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. □P<0.05, □□P<0.01, vs PMA group."

Table 5

Effects of AKBA and ATO combination on secretions of TNF-α and IL-1β by THP-1 cells and cell coculture system"

Figure 8

Effects of AKBA and ATO combination on phosphorylation of ERK1/2 and p38MAPK in HSFbs1: Control group; 2: TNF-α group; 3: TNF-α+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. △P<0.05, △△P<0.01, vs TNF-α group."

Figure 9

Effects of AKBA and ATO combination on phosphorylation of ERK1/2 and p38MAPK in THP-1 cells1: Control group; 2: PMA group; 3: PMA+AKBA+ATO group. Data were represented as $\overline{x}$±s, n=3. ▲P<0.05, ▲▲P<0.01, vs PMA group."

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