Study of anti-inflammatory activities of the pure compounds from Andrographis paniculata (burm.f.) Nees and their effects on gene expression.
In inflammation, the responses to noxious stimuli are controlled by the highly modulated interactions between various immune cells and chemical mediators. The purpose of this study is to evaluate and compare the anti-inflammatory effect of diterpenoids isolated from Andrographis paniculata, including dehydroandrographolide (AP1), andrographolide (AP2) and neoandrographolide (AP3), on the production of inflammatory cytokines and COX activities. Furthermore, the alteration of gene expression involved in this activity was investigated in the most potent compound to elucidate the other possible molecular mechanisms. AP1 (30.1 μM; 10 μg/ml) and AP2 (28.5 μM; 10 μg/ml) markedly inhibited COX-1 in ionophore A23187-induced human platelets. AP2 (28.5 μM) and AP3 (20.8 μM; 10 μg/ml) strongly suppressed the LPS-stimulated COX-2 activity in human blood. In addition, AP2 modulated the level of LPS-induced TNF-α, IL-6, IL-1β and IL-10 secretion in human blood in a concentration-dependent manner. The results revealed that AP2 exhibited the highest efficacy. Therefore, changes in the levels of mRNA transcripts by AP2 were further measured using human cDNA microarrays. The molecular response to AP2 was complex and mediated by various processes. Among the altered gene expressions, the genes involved in immune and inflammation processes were selectively down-regulated, such as cytokines and cytokine receptors (TNFSF14, TNF, TNFRSF6, and IL1A), chemokines (CCL8 and CXCL11), JAK/STAT signaling (JAK3 and STAT5A), TLRs family (TLR4 and TLR8) and NF-κB (NFKB1). Expression of some genes was validated using RT-PCR. The results demonstrated that AP1, AP2 and AP3 exhibited the anti-inflammatory effect by interfering COX and inflammatory cytokines and the underlying mechanisms of AP2 may be related to down-expression of genes involved in inflammatory cascade.
Parichatikanond
Warisara
W
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Suthisisang
Chuthamanee
C
Dhepakson
Panadda
P
Herunsalee
Angkana
A
D000328:Adult; D035685:Andrographis / Q000737:chemistry*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology; D000001:Calcimycin / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000276:immunology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects*; D005960:Glucosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018121:Receptors, Cytokine / Q000276:immunology / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051193:Toll-Like Receptors / Q000032:analysis / Q000276:immunology; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004224:Diterpenes; D005960:Glucosides; D018121:Receptors, Cytokine; D013764:Tetrahydronaphthalenes; D051193:Toll-Like Receptors; D000001:Calcimycin; C030419:andrographolide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C478098:dehydroandrographolide; C082497:neoandrographolide