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).
Toll-like receptors (TLRs) 3 play a critical role in innate immune responses in mammals through the recognition of conserved molecular patterns associated with different microorganisms (1-6). Upon binding of TLR ligands, all of the TLRs except TLR3 recruit the adaptor molecule MyD88 through the TIR domain, mediating the so-called MyD88-dependent pathway (7). MyD88 then recruits serine-threonine kinases IRAK4 (IL-1 receptor-associated kinase 4) and . Although IRAK4 is the kinase that functions upstream of and phosphorylates IRAK, the phosphorylated IRAK mediates the recruitment of TRAF6 to the receptor complex (13,14). Upon phosphorylation of IRAK, the IRAK⅐TRAF6 complex dissociates from the receptor complex to interact with and activate downstream kinases, leading to the activation of NFB and JNK (14,15).We recently reported the co-existence of the two parallel IL-1-mediated TAK1-dependent and MEKK3-dependent signaling pathways for NFB activation ( Fig. 1) (16). These two pathways are regulated at the level of IRAK modification. The TAK1-dependent pathway causes IKK␣/ phosphorylation and IKK activation, leading to classic NFB activation through IB␣ phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway induces IKK␥ phosphorylation and IKK␣ activation, resulting in NFB activation through IB␣ phosphorylation and subsequent dissociation from NFB but without IB␣ degradation. It is important to note that we recently found that TLR8-mediated NFB and JNK activation are TAK1-independent and MEKK3-dependent, suggesting a regulatory mechanism at the level of receptor complexes that determines the usage of TAK1-dependent versus MEKK3-dependent pathways in IL-1R/TLR signaling.IRAK4 has been shown to play an essential role in TLR-mediated signaling (9,10). IRAK4 kinase-inactive knock-in mice were completely resistant to LPS-and CpG-induced shock, due to impaired TLR-mediated induction of pro-inflammatory cytokines and chemokines (17)(18)(19)(20). Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R-mediated NFB activation, a reduction of LPS-, R848-, and IL-1-mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow (BM)-derived macrophages from IRAK4 kinase-inactive knock-in mice (18,20). These in vivo studies indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses (21).
Cytotoxicity and proinflammatory cytokine expression in response to eluates of a ceramic-polymer composite biomaterial in cultured human hs-27 cells; possible application for bone regeneration. Folia Biologica (Kraków) 66: 159-164.The idea of bone tissue regeneration calls for the development of new biomaterials. We designed a novel ceramic-polymer composite material that expresses the feature of drug carrier to restore facial and cranial bone defects. The ceramic phase consists of BCP with different proportions of HAp/â-TCP, while the polymer phase is poly(D, L-lactide) which is a carrier for clindamycin. The purpose of this study was to determine whether the eluates of the designed biomaterial have the potential to cause inflammatory response or express cytotoxicity in vitro. The elution was carried out for 24 hours or 6 days. Cells were incubated for 24 or 48 h with eluates of six types of materials: HP1 group (HAp with polylactide in composition 61%-39%); HP2 group (HAp with polylactide in composition 80%-20%); HPC group (HAp with polylactide and clindamycin); BP group (BCP with polylactide); BPC group (BCP with polylactide and clindamycin); B group (BCP). Cytotoxicity was determined with a commercial cytotoxicity kit on human fibroblasts from the hs-27 cell line. ELISA was used to measure cytokine expression for pro-inflammatory IL-6 and IL-8. Eluates of the novel ceramic-polymer composite material with the feature of a drug carrier (BCP and polylactide with clindamycin) did not produce a cytotoxic effect in the human fibroblast hs-27 cell line, nor did any of the tested biomaterials. The tested materials did not influence the production of pro-inflammatory cytokines. Therefore the novel ceramic-polylactide composite material may be further tested in vivo as a promising alternative for known biomaterials in bone defect reconstruction.
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