Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disease that affects over 1 percent of the population worldwide [1
]. The commonly used drugs such as nonsteroidal anti-inflammatory drugs (NSAIDS) and biologics (e.g., antitumor necrosis-α
antibody) are effective in alleviating the symptoms of the disease. However, the prolonged use of these drugs is associated with severe adverse reactions [2
]. In addition, these drugs are expensive, and not all patients respond well to them. In view of these limitations, it is essential to continue the search for safer and less expensive alternatives to the conventionally used drugs [4
]. Natural plant products represent a promising group of therapeutic agents for arthritis. However, one of the major concerns in seriously considering these products for therapeutic purposes is that the mechanisms of action of many of them are poorly defined, if at all.
RA primarily targets the joints, and is characterized by inflammatory synovitis mediated by leukocytes and the proinflammatory cytokines secreted by them [1
]. The migration of leukocytes from the peripheral blood into the joints is directed by chemotactic cytokines (chemokines) [7
]. Furthermore, severe arthritis is associated with cartilage and bone damage, which is mediated in part by the matrix-degrading enzymes, matrix metalloproteinases (MMPs) [8
]. Therefore, chemokines and MMPs are attractive targets for the treatment of arthritis [10
Chemokines are small, biologically active molecules that attract specific populations of inflammatory cells and regulate their trafficking to the site of inflammation. Among the chemokines that play an important role in inflammation, including RA, are regulated upon activation, normal T cell expressed, and secreted (RANTES), also known as chemokine C-C motif ligand 5 (CCL5); monocyte chemotactic protein-1 (MCP-1), or CCL2; macrophage inflammatory protein-1α
), or CCL3; and growth regulated oncogene-keratinocyte chemoattractant (GRO/KC), or chemokine C-X-C motif ligand 1 (CXCL1) [12
]. The chemokines interact with their receptors which belong to seven-transmembrane G-protein-coupled molecules. Henceforth, for simplicity we will refer to the 4 chemokines tested in this study by their common names (RANTES, MCP-1, MIP-1α
, and GRO/KC).
MMPs are a group of zinc-dependent endopeptidases that can degrade the extracellular matrix (ECM). Among the MMPs, MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are especially important in collagen degradation [16
]. The expression/activity of MMPs can be modulated by the proinflammatory cytokines interlukin-6 (IL-6) and IL-17 that are expressed in the synovial tissue and synovial fluid in the joints of RA patients [8
Huo-luo-xiao-ling dan (HLXL), a traditional Chinese herbal formula, and its modified versions have been used in folk medicine over centuries to treat inflammatory arthritis or joint pain, referred to as the “Bi syndrome
]. The use of a combination of multiple herbs is designed to exploit the additive or synergistic activities of individual herbs, as well as to balance or neutralize the toxic effects of certain herbal components by others in the mixture [20
]. In our previous studies in animal models of arthritis, we have shown that oral administration of modified HLXL, a well-characterized herbal mixture [21
], to rats can attenuate inflammatory paw edema as well as the swelling and pain associated with clinical arthritis. In addition, HLXL modulates the balance of pro- versus anti-inflammatory cytokines [24
]. In this study, we examined the effect of HLXL on specific chemokines and MMPs, which play an important role in the pathogenesis of AA [25
]. As the expression/activity of certain chemokines as well as MMPs is influenced significantly by the proinflammatory cytokines (IL-17 and IL-6), we also tested the effect of HLXL on these two cytokines. We observed that HLXL treatment of arthritic rats attenuates the progression of AA by inhibiting chemokines (RANTES, MCP-1, MIP-1α
, and GRO/KC), MMPs (MMP-2 and MMP-9), and cytokines (IL-6 and IL-17). To the best of our knowledge, this is the first report describing these HLXL-induced changes in arthritis.