Toll-like receptors (TLRs) are best known for their ability to recognize microbial or viral components and initiate innate immune responses. We showed here that TLRs and their coreceptors were expressed by multipotential hematopoietic stem cells, whose cell cycle entry was triggered by TLR ligation. TLR expression also extended to some of the early hematopoietic progenitors, although not the progenitor cells dedicated to megakaryocyte and erythroid differentiation. TLR signaling via the Myd88 adaptor protein drove differentiation of myeloid progenitors, bypassing some normal growth and differentiation requirements, and also drove lymphoid progenitors to become dendritic cells. CD14 contributed to the efficiency of lipopolysaccharide (LPS) recognition by stem and progenitor cells, and LPS interacted directly with the TLR4/MD-2 complex on these cells in bone marrow. Thus, the preferential pathogen-mediated stimulation of myeloid differentiation pathways may provide a means for rapid replenishment of the innate immune system during infection.
The incidence of obesity which leads to insulin resistance (IR) and metabolic disorder is increasing in developing countries, including Indonesia. Male adults have a higher risk of abdominal obesity than females. This is associated with cardiometabolic disorders. Several anthropometric measurements have been proposed to predict IR. The aim of this study was to investigate whether body mass, body mass index (BMI), waist circumference (WC), body fat percentage (BF) or visceral fat level (VF) could become a better predictor of IR in healthy young male adults. A total of 140 healthy young male adults ranging from 18–25 years were recruited in the study. Insulin resistance was measured by calculating their Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Subjects with a HOMA-IR value ≥75th percentile, with cut off 3.75, were defined as IR. Anthropometric measurements including body weight, BMI, and WC were performed, whereas BF and VC were measured using bioelectrical impedance analysis (BIA). IR had a strong correlation with body weight, BMI, WC, BF, and VF. In the area under the curve of body mass, BF and VF were slightly greater than WC and BMI. Anthropometric measurements correlated strongly with IR but body weight, BF, VF had a stronger correlation than WC and BMI in healthy young male adults.
We have established an agonistic monoclonal antibody, UT12, that induces stimulatory signals comparable to those induced by lipopolysaccharide (LPS) through Toll-like receptor 4 and MD-2. UT12 activated nuclear factor B and induced the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) in peritoneal exudative cells. In addition, mice injected with UT12 rapidly fell into endotoxin shock concomitant with the augmentation of serum TNF-␣ and IL-6 levels, followed by death within 12 h. On the other hand, when the mice were pretreated with a sublethal dose of UT12, the mice survived the subsequent lethal LPS challenges, with significant suppression of serum TNF-␣ and IL-6, indicating that UT12 induced tolerance against LPS. This effect of UT12 was maintained for at least 9 days. In contrast, the tolerance induced by LPS continued for less than 3 days. These results illuminate a novel potential therapeutic strategy for endotoxin shock by the use of monoclonal antibodies against the Toll-like receptor 4/MD-2 complex.Lipopolysaccharide (LPS) is a glycolipid component of the gram-negative bacterial cell wall and induces various host responses, including the production of proinflammatory cytokines. When they are appropriately produced, these cytokines, such as tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), activate host immunity to fight off bacteria. The excessive proinflammatory cytokines produced in response to large amounts of LPS, however, can provoke extreme systemic inflammation and often cause lethal endotoxin shock.Animals pretreated with a sublethal dose of LPS become tolerant to subsequent challenges with a lethal dose of LPS and display reduced mortality. This phenomenon is called LPS tolerance and is defined as the reduced capacity of the host or cultured macrophage/monocyte to respond to LPS following initial stimulation (6,26). It has also been reported that bacterial or fungal removal is improved during the tolerant state, despite attenuated cytokine production (14,20). Therefore, LPS tolerance is regarded as a reasonable response that simultaneously manages both the clearance of pathogens and host protection from excess inflammation.Here we report on the induction of long-term LPS tolerance realized by an agonistic monoclonal antibody (MAb) against the Toll-like receptor 4 (TLR4)/MD-2 complex. Mice pretreated with this MAb showed significant survival advantages compared with the survival of LPS-pretreated mice. MATERIALS AND METHODSMice. C3H/HeN, C3H/HeJ, ddY, and SCID mice were from Japan SLC (Hamamatsu, Shizuoka, Japan). C57BL/6 mice were from Charles River Japan (Yokohama, Kanagawa, Japan). A TLR4-knockout mouse strain with the C57BL/6 background (12) was a kind gift from S. Akira (Osaka University, Osaka, Japan). All animals were maintained in the Center for Laboratory Animals at Saga Medical School and were treated in accordance with the regulations of the Scientists Center for Animal Welfare.Cell culture. All the cells were cult...
Ligands for toll-like receptors (TLR) are known to induce a variety of immune responses. Selective induction of desirable responses would be important for the treatment of individual diseases with various pathogenesis. For this purpose, we established six MAbs against the TLR4/MD-2 complex (UT MAbs) from TLR4(-/-) mice or MD-2(-/-) mice. Three MAbs (UT12, 18, and 22) induced NF-kappaB activation and production of pro-inflammatory cytokines, but the other three (UT15, 41, and 49) did not induce such cell responses. Unlike lipopolysaccharide (LPS), agonistic UT MAbs did not require serum components for the functions. UT41 and UT49 recognized TLR4 in the absence of MD-2. On the other hand, the other four MAbs reacted to the TLR4/MD-2 complex, but not to solo TLR4. Agonistic UT MAbs shared the epitopes, but non-agonistic UT15 reacted to distinct epitope on the complex. UT MAbs appear to be useful analyzing the molecular mechanism of TLR signaling and will contribute to the development of novel immunotherapies.
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