Mast cell-dependent anorexia induced by mucosal activation of Toll-like receptor
Widodo Judarwanto. Picky Eaters & Grow Up Clinic, Jakarta Indonesia
Systemic viral infections produce a highly regulated set of responses in sickness behavior, such as fever, anorexia, and adipsia. Toll-like receptor (TLR)7, activated by viral RNA during infection, potently stimulates the innate and adaptive immune responses that aid in viral clearance. However, the physiological consequences of TLR7 activation have not been thoroughly studied. In these experiments, we used a potent synthetic TLR7 ligand, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy)adenine (SM360320; 1V136), to investigate the consequences of TLR7 activation in genetically defined strains of mice. Administration of the drug by the nasal, intragastric, or intraperitoneal routes caused transient hypophagia, hypodypsia, and hypothermia.
Analyses of mutant mouse strains indicated that these effects were dependent on the expression of TLR7, its adaptor protein MyD88, and TNF-alpha, and independent of IL-1beta, IL-6 and cyclo-oxygenase-1 (COX1). Partial roles were also implied for mast cells and COX2. Although plasma TNF-alpha levels were significantly higher after systemic drug delivery, the behavioral effects were maximal when the agent was administered to the mucosa. Tissue and mucosal mast cells are known to express high levels of TLR7 and to rapidly release TNF-alpha upon TLR7 ligation. Mice deficient in tissue mast cells, W/W(v), had significantly less anorexia after TLR7 activation, and this response was restored with mast cell reconstitution. These study suggest that tissue mast cells may play a role in the anorexia induced by mucosal activation of TLR7.
IL-4 and 8-mercaptoguanosine (8-SGuo) stimulation of CD38-activated B cells induces mu to gamma1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Although some of signaling events initiated by IL-4 in activated B cells have been characterized, the involvement of TLR/MyD88 and Btk pathway in IL-4-dependent mu to gamma1 CSR has not been thoroughly evaluated. In this study, we characterized receptors for 8-SGuo and differential roles of 8-SGuo and IL-4 in the induction and mu to gamma1 CSR and IgG1 production. The role of TLR7 and MyD88 in 8-SGuo-induced AID expression and mu to gamma1 CSR was documented, as 8-SGuo did not act on CD38-stimulated splenic B cells from Tlr7(-/-) and Myd88(-/-) mice. CD38-activated B cells from Btk-deficient mice failed to respond to TLR7 ligands for the AID expression and CSR, indicating that Btk is also indispensable for the system. Stimulation of CD38-activated B cells with 8-SGuo induced significant AID expression and DNA double strand breaks, but IL-4 stimulation by itself did not trigger mu to gamma1 CSR.
Intriguingly, the mu to gamma1 CSR in the B cells stimulated with CD38 and 8-SGuo totally depends on IL-4 stimulation. Similar results were obtained in the activated B cells through BCR and loxoribine, a well-known TLR7 ligand, in place of 8-SGuo. In vivo administration of TLR7 ligand and anti-CD38 antibody induced the generation of CD138(+) IgG1(+) cells. These results indicate that TLR7 is a receptor for 8-SGuo and plays an essential role in the AID and Blimp-1 expression; however it is not enough to complete mu to gamma1 CSR in CD38-activated B cells. IL-4 may be required for the induction of DNA repair system together with AID for the completion of CSR.
Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4
Toll-like receptors (TLRs) are mammalian homologues of the Drosophila Toll receptors and are thought to have roles in innate recognition of bacteria. We demonstrated that TLR 2, 4, 6, and 8 but not TLR5 were expressed on mouse bone marrow-derived mast cells (BMMCs). Using BMMCs from the genetically TLR4-mutated strain C3H/HeJ, we demonstrated that functional TLR4 was required for a full responsiveness of BMMCs to produce inflammatory cytokines (IL-1beta, TNF-alpha, IL-6, and IL-13) by LPS stimulation. TLR4-mediated stimulation of mast cells by LPS was followed by activation of NF-kappaB but not by stress-activated protein kinase/c-Jun NH2-terminal kinase signaling. In addition, in the cecal ligation and puncture-induced acute septic peritonitis model, we demonstrated that genetically mast cell-deficient W/W(v) mice that were reconstituted with TLR4-mutated BMMCs had significantly higher mortality than W/W(v) mice reconstituted with TLR4-intact BMMCs. Higher mortality of TLR4-mutated BMMC-reconstituted W/W(v) mice was well correlated with defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity. Taken together, these observations provide definitive evidence that mast cells play important roles in exerting the innate immunity by releasing inflammatory cytokines and recruitment of neutrophils after recognition of enterobacteria through TLR4 on mast cells.
norexia, adipsia, and depressed motor activity during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1.
Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of Mycoplasmas that causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs)-2 and -6. The characterize the ability of MALP-2 and a synthetic analog fibroblast-stimulating lipopeptide-1 (FSL-1; represents the NH2-terminal sequence of a lipoprotein from M. salivarium) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behavior, such as depressed motor activity, anorexia, and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for 3 days by use of telemetry devices in several groups of rats treated with MALP-2/FSL-1 or the respective control solutions. Intraperitoneal injections of FSL-1 caused fever at doses of 10 or 100 microg/kg, which was preceded by a pronounced phase of hypothermia in response to a dose of 1,000 microg/kg. The maximal fever (a peak of 1.5 degrees C above baseline) was caused by the 100 microg/kg dose with almost identical responses to both MALP-2 and FSL-1. Fever was accompanied by pronounced rises of the proinflammatory cytokines TNF and IL-6 in plasma.
Treatment with the TLR-2 and -6 agonists further induced a dose-dependent manifestation of anorexia and adipsia, as well as a reduction of motor activity. We could thus demonstrate that activation of TLR-2 and -6 can induce systemic inflammation in rats accompanied by the classical signs of brain-controlled illness responses.
- Hayashi T, et al. Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7. Am J Physiol Regul Integr Comp Physiol. 2008 Jul;295(1):R123-32.
- Tsukamoto Y, et al. Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production. Mol Immunol. 2009 Apr;46(7):1278-88. Epub 2009 Jan 20.
- Supajatura V, et al. Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4. J Immunol. 2001 Aug 15;167(4):2250-6.
- Hübschle T, et al. Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1. Am J Physiol Regul Integr Comp Physiol. 2006 Jan;290(1):R180-7.
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