Stimulation of Interleukin 1 Beta and Interleukin 6 Production by the Environmental Contaminant Tributyltin Utilizes Toll-Like Receptor 4 and Toll-Like Receptor 1/2
Toll-like receptors (TLR) are integral for activating the innate immune system, which is responsible for initiating responses against the first encounter with infectious organisms by recognizing pathogen associated molecular patterns (PAMPs) as well as products released from cell damage due to injury referred to as damage associated molecular patterns (DAMPs). MAP Kinases are downstream signaling components activated by TLRs that lead to the production of chemokines, type I interferons, and pro-inflammatory cytokines, such as interleukin 1β (IL-1β) and interleukin 6 (IL-6). IL-1β and IL-6 are pro-inflammatory cytokines necessary for an appropriate response to injury or infection. Dysregulation of IL-1β or IL-6 levels lead to chronic inflammation, which is implicated in the development of diseases such as atherosclerosis, cancer, and autoimmunity. Tributyltin (TBT) is an environmental contaminant known to be an endocrine disruptor and widely known for its use as a biocide and in anti-fouling paints. Previous studies have found that exposure to TBT, which is present in human blood, increases the secretion and intracellular concentrations (production) of the pro-inflammatory cytokines IL-1β and IL-6 in peripheral blood mononuclear cells (PMBCs) and this increase requires MAPK activation. The current study examines whether the upstream regulators of MAPK activation in immune cell production of IL-1β and IL-6, TLRs, are also required for TBT to induce increases in IL-1β and IL-6 by inhibiting either TLR4 and TLR1/2 with 1 µM of TAK242 (TLR4 inhibitor) or 8 µM CU CPT 22 (TLR1/2 inhibitor). The ability of TBT (100, 50, and 25 nM) to cause increased production of IL-1β or IL-6 after 24 h of exposure was examined using ELISA and western blot. Results indicate that when either TLR4 or TLR1/2 are inhibited by TAK242 or CU CPT 22, there is a decrease in TBT-induced production of both IL-β and IL-6. This suggests that TBT utilizes the TLRs to stimulate IL-1β and IL-6 production.
"Stimulation of Interleukin 1 Beta and Interleukin 6 Production by the Environmental Contaminant Tributyltin Utilizes Toll-Like Receptor 4 and Toll-Like Receptor 1/2"
ETD Collection for Tennessee State University.