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Abamectin, a broad-spectrum antiparasitic agent, has been shown to exert an anti-inflammatory effect, in vitro, by down regulating both the nuclear transcription factor kappa-B and the mitogen-activated protein kinase (MAPK) activation pathway. In this study, we investigated the role of abamectin in acute lung injury (ALI) induced by Lipopolysaccharide (LPS), and the invovment of MAPK and NF-κB. BALB/C mice were administered abamectin (PBS) orally, followed by a dose of 0.5 mg/kg of LPS. After 10 h, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF) were measured using enzyme-linked immunosorbent assay. The number of total cells, neutrophils, and macrophages in the BALF were determined. The right lung was then excised for histological examination and analysis of myeloperoxidase (MPO) activity. Phosphorylation of MAPK family and IκB were detected by western blot. We found that 2 mg/kg of abamectin had significant protective effects on ALI. Mice treated with LPS alone showed markedly increased TNF-α and IL-6 levels in the BALF. In addition, not only was the W/D ratio of lung tissue significantly decreased, the number of total cells, neutrophils and macrophages in the BALF was also significantly reduced 11 h after treatment with abamectin. Furthermore, p38MAPK, ERK, and IκB were activated in 10 h after LPS treatment, which could be blunted by Abamectin. These results indicate that abamectin could attenuate inflammatory injury induced by LPS through MAPK and NF-κB passway.

Florfenicol, an antibiotic commonly used to treat infections, has previously been shown to modulate lipopolysaccharide (LPS)-induced early cytokine responses by blocking the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the effects of florfenicol on nitric oxide (NO) and prostaglandin E₂ (PGE₂) production as well as on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated murine RAW 264.7 macrophages. We also analysed the effects of florfenicol on mitogen-activated protein kinase (MAPK) pathways. Florfenicol significantly inhibited LPS-induced NO and PGE₂ production. Consistent with these observations, mRNA and protein expression of iNOS and COX-2 were also inhibited by florfenicol in a dose-dependent manner. Furthermore, phosphorylation of p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) in LPS-stimulated RAW 264.7 cells was suppressed by florfenicol. However, c-Jun N-terminal kinase (JNK) phosphorylation remained unaffected. Using specific inhibitors of ERK and p38, we found that florfenicol may inhibit NO and PGE₂ mostly through ERK and p38 pathway. These results suggest that florfenicol inhibits NO and PGE₂ production in conjunction with an inhibition of iNOS and COX-2 expression, at least partially via suppression of ERK1/2 and p38 MAPK phosphorylation.

Lipopolysaccharide (LPS) can induce mouse macrophages to produce a number of cytokines and other inflammatory mediators. Immunopharmacological studies can provide new information on the immunomodulatory activities of some drugs, including their effect on cytokine productions. For this reason, we first investigated the efficacy of avermectin on cytokine levels induced by LPS in vitro, and we found that avermectin can significantly regulate tumor necrosis factor alpha, interleukin (IL)-1beta and IL-10, but has no significant effect on IL-6. We further investigated the effects of the drug on the major signal transduction pathways associated with inflammation: nuclear transcription factor kappa-B (NF-kappaB) and the mitogen-activated protein (MAP) kinases, extracellular signal regulated kinase, p38 and c-Jun N-terminal kinase (JNK). RAW 264.7 cells were pretreated with 0.625, 1.25 or 5 mg/L avermectin 1 h prior to treatment with 1 mg/L LPS. Thirty minutes later, cells were fixed, and NF-kappaB activation was measured by immunocytochemical analysis, or cells were collected and MAP-kinase activation was measured by western blot. Signal transduction studies showed that avermectin significantly inhibits NF-kappaB p65 translocation into the nucleus and inhibits JNK and p38 phosphorylation protein expression. Therefore, avermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kappaB and MAP-kinase in RAW 264.7 cells.

Many traditional Chinese medicines have been used as immunomodulators that act as either immunosuppressants or immunostimulators. Recently, our lab successfully isolated a monomer telocinobufagin (TCB) from the chloroform extract of Chan Su (Venenum Bufonis). In the present paper, we evaluated the immunomodulatory effects of this compound in vitro. We found that TCB significantly stimulates splenocyte proliferation when administered alone or in combination with polyclonal T-cell mitogens concanavalin A (Con A) and lipopolysaccharide. Telocinobufagin markedly enhances natural killer cell and peritoneal macrophage activation. Telocinobufagin increases the percentage of CD4, CD8 positive cells within a population of splenocytes. Moreover, we found that the level of several Th1 cytokines, including interleukin-2 (IL-2), interleukin-12 (IL-12), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), are significantly increased after TCB treatment, while the level of the Th2 cytokine interleukin-4 (IL-4) is significantly decreased. As a result, the ratio of Th1/Th2 is significantly increased. Taken together, these results indicate that TCB has potential immune system regulatory effects and suggest that this compound could be developed as a novel immunotherapeutic agent to treat cancer and other immune-mediated diseases, and it may become a new immunomodulatory agent in many regions.