Abstract
BackgroundImmunomodulatory effects of Tinospora crispa have been investigated due to its traditional use to treat several inflammatory disorders associated to the immune system. The present study reports the underlying mechanisms involved in the stimulation of 80% ethanol extract of T. crispa stems on pro-inflammatory mediators release in lipopolysaccharide (LPS)-primed U937 human macrophages via MyD88-dependent pathways.MethodsRelease of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and production of prostaglandin E2 (PGE2) were determined by using enzyme-linked immunosorbent assay (ELISA). Immunoblot technique was executed to determine the activation of MAPKs molecules, NF-κB, PI3K-Akt and cyclooxygenase-2 (COX-2) protein. Determination of pro-inflammatory cytokines and COX-2 relative gene expression levels was by performing the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). A reversed-phase HPLC method was developed and validated to standardize the T. crispa extract and chemical profiling of its secondary metabolites was performed by LC-MS/MS.ResultsQualitative and quantitative analyses of chromatographic data indicated that syringin and magnoflorine were found as the major components of the extract. T. crispa-treatment prompted activation of NF-κB by enhancing IKKα/β and NF-κB (p65) phosphorylation, and degradation of IκBα. The extract upregulated COX-2 protein expression, release of pro-inflammatory mediators and MAPKs (ERK, p38 and JNK) phosphorylation as well as Akt dose-dependently. T. crispa extract also upregulated the upstream signaling adaptor molecules, toll-like receptor 4 (TLR4) and MyD88. T. crispa-treatment also upregulated the pro-inflammatory markers mRNA expression.ConclusionThe results suggested that T. crispa extract stimulated the MyD88-dependent signaling pathways by upregulating the various immune inflammatory related parameters.
Highlights
Immunomodulatory effects of Tinospora crispa have been investigated due to its traditional use to treat several inflammatory disorders associated to the immune system
In accordance with the findings of the release of cytokines and mRNA expression, the present results proved that T. crispa extract enhanced the release of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) and mRNA expression through upregulating the nuclear factorkappa B (NF-κB) signaling activation
LPS selectively binds with the toll-like receptor 4 (TLR4), which further triggers the activation of upstream adaptor molecule known as myeloid differentiation primary response gene 88 (MyD88) in macrophages
Summary
Immunomodulatory effects of Tinospora crispa have been investigated due to its traditional use to treat several inflammatory disorders associated to the immune system. Immunomodulators, mostly organic synthetics such as alkylating agents, steroidal and non-steroidal drugs including glucocorticoids as well as biological agents like cytokine inhibitors, interferon inducers, polyclonal and monoclonal antibodies have been presently used to heal immune-related ailments. Their clinical use as immunomodulators, i.e., immunosuppressants or immunostimulants are with limitations due to their cytotoxicity and severe adverse effects. The immunomodulating effects of medicinal plants have been attributed to their phytochemicals like polysaccharides, glycosides, flavonoids, alkaloids, lactones, and terpenoids [1,2,3,4] They are broadly used in treating several immune disorders, including inflammatory complaints, autoimmune ailments, as well as cancer. In the last few decades, phytochemicals have attracted great interest as sources of natural immunomodulators, which are less toxic and inexpensive products compared to synthetic therapeutic agents [3]
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