Toll-like receptors (TLRs) TLR1, TLR2, TLR4, and TLR6 are evolutionarily conserved, highly homologous, and localized to plasma membranes of host cells and recognize pathogen-associated molecular patterns (PAMPs) derived from bacterial membranes. These receptors cooperate in a pairwise combination to elicit or inhibit the inflammatory signals in response to certain PAMPs. The other TLRs that are evolutionarily closely related and highly homologous are TLR7, TLR8, and TLR9. They are all confined to the membranes of endosomes and recognize similar molecular structures, the oligonucleotide-based PAMPs. However, the cooperative interactions among these receptors that may modulate the inflammatory signaling in response to their cognate agonists are not reported. We report here for the first time the functional effects of one TLR on the other among TLR7, TLR8, and TLR9. The results indicate that TLR8 inhibits TLR7 and TLR9, and TLR9 inhibits TLR7 but not vice versa in HEK293 cells transfected with TLRs in a pairwise combination. This is concluded by selectively activating one TLR over the other by using small molecule TLR agonists. We also show that these inhibitory interactions are the result of direct or indirect physical interactions between the TLRs. The murine TLR8 that does not respond to any known human TLR8 agonists also inhibits both murine and human TLR7. The implications of the inhibitory interactions among these TLRs in hostpathogen recognition and subsequent inflammatory responses are not obvious. However, given the complexity in expression pattern in a particular cell type and the variation in distribution and response to different pathogens and stress signals in different cell types, the inhibitory physical interactions among these TLRs may play a role in balancing the inflammatory outcome from a given cell type to a specific challenge.
Macrophages isolated from the peritoneal cavity of untreated mice and maintained in tissue culture synthesize and release prostaglandins when challenged with zymosan. These cells also selectively release lysosomal acid hydrolases under the same conditions. The major prostaglandins released into the media are found to be prostaglandins E1, E2 and 6-oxoprostaglandin F1a, whereas prostaglandin F2a is not detected. Macrophages isolated from mice that have received an intraperitoneal injection of thioglycollate broth are far less responsive to zymosan challenge. These cells require 300 microgram of zymosan to synthesize and release one-third the amount of prostaglandins released from non-stimulated macrophages exposed to 50 microgram of zymosan. In addition, thioglycollate-stimulated macrophages release less than 10% of their lysosomal acid hydrolases when exposed to 300 microgram of zymosan whereas non-stimulated cells release approximately 50% of these enzymes after treatment with 50 microgram of zymosan. The zymosan-stimulated synthesis and release of prostaglandins are completely inhibited by indomethacin, whereas the increased selective release of lysosomal acid hydrolases is not affected. Macrophages, unlike fibroblasts, do not synthesize and release prostaglandins when exposed to serum or to bradykinin.
The IL-1 2 /Toll receptors play essential roles in inflammation and innate immunity. The defining feature of members of the superfamily is a Toll/IL-1 receptor (TIR) domain on the cytoplasmic side of the receptors. The members of the IL-1 receptor subfamily contain three Ig domains in their extracellular regions (1). The other group in the superfamily is the recently identified pathogen-associated pattern recognition receptors, the Toll-like receptors (TLRs), 11 members of which contain two major domains characterized by extracellular leucine-rich repeats and an intracellular TIR domain (2-7).Much progress has been made in understanding the IL-1R-mediated signaling. Upon IL-1 stimulation, the TIR domaincontaining adaptor molecule MyD88 (8) is recruited to the TIR domain of the receptor complex, which then recruits serinethreonine kinases IRAK4 (IL-1 receptor associated kinase 4) (9, 10) and IRAK (11,12). Whereas IRAK4 is the kinase that functions upstream of and phosphorylates IRAK, the phosphorylated IRAK mediates the recruitment of TRAF6 to the receptor complex (13). IRAK-TRAF6 then leaves the receptor complex to interact with TAK1, a member of the mitogen-activated protein kinase kinase kinase family, and the proteins that bind to it, TAB1, TAB2, and TAB3 on the membrane (14, 15). TAK1 and TAB2 are phosphorylated on the membrane, followed by the formation and translocation of TRAF6-TAK1-TAB1-TAB2, from the membrane to the cytosol (15), where TAK1 is activated. Whereas genetic studies show that IRAK is required for the IL-1-induced activation of TAK1, in vitro biochemical analyses reveal that TRAF6-mediated ubiquitination may also play an important role in TAK1 activation (16). The activation of TAK1 eventually leads to the activation of IB kinase (IKK) by an unknown mechanism. Activated IKK phosphorylates IB proteins, which are degraded, releasing NF-B to activate transcription in the nucleus (17)(18)(19)(20). Activated TAK1 has also been implicated in the IL-1-induced activation of MKK6 and JNK (14). The definitive evidence for an essential role of TAK1 in IL-1 signaling is from studies with TAK1-deficient cells. Two groups (21,22) independently reported that TAK1 deficiency leads to a defect in IL-1 signaling. MEKK3 has also been implicated in IL-1-mediated IKK and JNK activation, possibly through its interaction with TRAF6 (23-25).
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