The Early Induction of Suppressor of Cytokine Signaling 1 and the Downregulation of Toll-like Receptors 7 and 9 Induce Tolerance in Costimulated Macrophages
نویسندگان
چکیده
Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88-dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance induced through the costimulation of individual TLR has not yet been established, although endosomal TLRs share signaling pathways with TLR4. In the present study, mouse macrophages were simultaneously stimulated with the TLR7 agonist, gardiquimod (GDQ), and the TLR9 agonist, CpG ODN 1826, to examine the mechanism and effector functions of macrophage tolerance. Compared with individual stimulation, the costimulation of both TLRs reduced the secretion of TNF-α and IL-6 through the delayed activation of the NF-κB pathway; notably, IL-10 remained unchanged in costimulated macrophages. This tolerance reflected the early induction of suppressor of cytokine signaling-1 (SOCS-1), according to the detection of elevated TNF-α secretion and restored NF-κB signaling in response to the siRNA-mediated abrogation of SOCS-1 signaling. In addition, the restimulation of each TLRs using the same ligand significantly reduced the expression of both TLRs in endosomes. These findings revealed that the costimulation of TLR7 and TLR9 induced macrophage tolerance via SOCS-1, and the restimulation of each receptor or both TLR7 and TLR9 downregulated TLR expression through a negative feedback mechanisms that protects the host from excessive inflammatory responses. Moreover, the insufficient and impaired immune response in chronic viral infection might also reflect the repeated and simultaneous stimulation of those endosomal TLRs.
منابع مشابه
Evaluation of Soluble Toll-Like Receptors 2, 4, 9 and Their Damps Signaling Molecules (HMGB1 & HSP70) in Breast Cancer Patients of Basrah Province
Introduction: Toll-Like Receptors (TLRs) are members of pattern recognition receptors that recognize various molecules, including pathogen-associated molecular patterns and dead-associated molecular patterns. These receptors are expressed by immune, non-immune, and tumor cells. Some TLRs are implicated in tumor progression, while others are involved in tumor suppression. Our study aimed to eval...
متن کاملEffect of valproic acid on JAK/STAT pathway, SOCS1, SOCS3, Bcl-xL, c-Myc, and Mcl-1 gene expression, cell growth inhibition and apoptosis induction in human colon cancer HT29 cell line.
Background and aim: Cytokines are a large family of protein messengers. These proteins induce various cellular responses. Janus kinases (JAKs) are mediators of cytokine, activated JAKs phosphorylate signal transducers, and activators of transcription (STAT) proteins that regulate cell differentiation, proliferation, and apoptosis. Aberrant JAK/STAT signaling is involved in the oncogenesis of se...
متن کاملP-157: TLR5 Gene Expression in Endometrium of Women with Unexplained Recurrent Spontaneous Abortion
Background: Recurrent spontaneous abortion (RSA) is usually defined as three or more consecutive pregnancy losses before 20th week of gestation. Although different factors are considered as etiology of RSA but in some cases, despite of extensive work up, the cause of RSA remains unknown which called unexplained RSA. Immunological factors are suggested as etiological factors of unexplained RSA. ...
متن کاملP-172: Intracellular Toll Like Receptors Expression in Endometriosis
Background: Endometriosis is a complex disease that profoundly affects the quality of life in many women. This disease affects roughly one in ten women of reproductive age. Endometriosis induces a variable amount of inflammatory reaction in pelvic environment. An active immune system needs to recognize these inflammatory agents. Rapid innate immune system defenses against infections involve the...
متن کاملEndoplasmic reticulum stress regulates inflammation in adipocyte of obese rats via toll-like receptors 4 signaling
Objective(s): To explore whether endoplasmic reticulum (ER) stress regulates inflammation in adipose tissue of obese rats via TLR4 signaling. Materials and Methods: Sprague Dawley rats were randomly divided into four groups, and body weight, food intake, and free fatty acids (FFA) were measured. Real-time PCR and Western blot were used to determine mRNA or protein expression of TLR4, TRAF6, IKK...
متن کامل