Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia

González-Serrano, María Edith; Estrada-Garcı́a, Iris; Mogica-Martínez, Dolores; Garay, Alejandro G Gonzalez; López‐Herrera, Gabriela; Berrón-Ruíz, Laura; Espinosa‐Padilla, Sara Elva; Yamazaki‐Nakashimada, Marco Antonio; Vargas-Hernández, Alexander; Santos-Argumedo, Leopoldo; Estrada‐Parra, Sergio; Espinosa-Rosales, Francisco

doi:10.1007/s10875-012-9706-z

Cited by 26 publications

(19 citation statements)

References 27 publications

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“…Finally, one study reported that Btk deficiency led to increased TLR-dependent IL12, but decreased TNF secretion in both thioglycollate-elicited peritoneal and bone marrow derived macrophages(13). Similar to the data in mice, human monocytes derived from patients lacking functional Btk have been shown to exhibit decreases(2, 14),increases(15, 16) and no change(17) in TLR-dependent pro-inflammatory cytokine secretion. Taken together, these results demonstrate that Tec kinases can positively and negatively regulate secretion of pro-inflammatory cytokines in response to TLR activation in macrophages; however, the reasons for the observed differences in polarity of their effect has not been clearly established.…”

Section: Introductionsupporting

confidence: 70%

The Tec Kinase–Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages

Tampella¹,

Kerns²,

Niu³

et al. 2015

The Journal of Immunology

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Previous work has shown conflicting roles for Tec family kinases in regulation of Toll-like receptor (TLR)-dependent signalling in myeloid cells. In the present study, we performed a detailed investigation of the role of Btk and Tec kinases in regulating TLR signalling in several types of primary murine macrophages. We demonstrate that primary resident peritoneal macrophages deficient for Btk and Tec secrete less pro-inflammatory cytokines in response to TLR stimulation than wild type cells. In contrast, we found that bone marrow-derived and thioglycollate-elicited peritoneal macrophages deficient for Btk and Tec secrete more pro-inflammatory cytokines than wild type cells. We then compared the phosphoproteome regulated by Tec kinases and lipopolysaccharide in primary peritoneal and bone marrow derived macrophages. From this analysis we determined that Tec kinases regulate different signalling programs in these cell types. In additional studies using bone marrow-derived macrophages, we find that Tec and Btk promote phosphorylation events necessary for immunoreceptor-mediated inhibition of TLR signalling. Taken together, our results are consistent with a model where Tec kinases (Btk, Tec, Bmx) are required for TLR-dependent signalling in many types of myeloid cells. However, our data also support a cell type-specific TLR-inhibitory role for Btk and Tec that is mediated by immunoreceptor activation and signalling via PI3K.

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Section: Introductionsupporting

confidence: 70%

The Tec Kinase–Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages

Tampella¹,

Kerns²,

Niu³

et al. 2015

The Journal of Immunology

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“…This finding supports a role for Btk in signaling via the TLR2,6 molecules. Previous data indicated that Src family kinases including c-Src regulated Btk activation [43], [44]. Therefore, activation of Btk was expected to be a consequence of c-Src activation in MALP-2-treated cells.…”

Section: Resultsmentioning

confidence: 94%

“…Btk is a non-receptor tyrosine kinase, and have been implicated in a double shift to control immune response [43]. To investigate its role in MALP-2 induced signaling, THP-1 cells were stimulated with MALP-2 for various lengths of time, and endogenous Btk was assessed for phosphorylation in the tyrosine residues at Tyr223, which was necessary for full activation of Btk [37].…”

Section: Resultsmentioning

confidence: 99%

Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

et al. 2014

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AimsThis study is to investigate the mechanisms by which macrophage-activating lipopeptide-2 (MALP-2) induces heme oxygenase (HO)-1, a cytoprotective enzyme that catalyzes the degradation of heme, in human monocytes.MethodsHuman monocytic THP-1 cells were cultured for transient transfection with plasmids and stimulation with MALP-2 for indicative time intervals. After incubation with MALP-2, cells were collected and disrupted, before being tested for promoter activity using luciferase assay. For analysis of proteins, immunoreactive bands were detected using an enhanced chemiluminescence Western blotting system, and the band intensity was measured by densitometryic analysis. For the detection of co-immunoprecipitation, SDS-PAGE was performed and the membranes were probed using respective antibodies. To investigate the cellular localization of NF-E2-related factor 2 (Nrf2), cells underwent immunofluorescence staining and confocal microscopy, and were analyzed using electrophoretic mobility shift assay.ResultsMALP-2-induced HO-1 expression and promoter activity were abrogated by transfection with dominant negative (DN) plasmids of TLR2 and TLR6, or their neutralizing antibodies. However, inhibition of MyD88 or transfection with the DN-MyD88 was insufficient to attenuate HO-1 expression. In contrast, mutation or silencing of MyD88 adapter-like (Mal) by DN-Mal or siRNA almost completely blocked HO-1 induction. Btk, c-Src and PI3K were also involved in MALP-2-induced HO-1 expression, as revealed by specific inhibitors LFM-A13, PP1 and LY294002, or by transfection with siRNA of c-Src. MALP-2-induced activation of PI3K was attenuated by transfection with DN mutant of Mal, and by pretreatment with LFM-A13 or PP1. Furthermore, MALP-2 stimulated the translocation of Nrf2 from the cytosol to the nucleus and Nrf2 binding to the ARE site in the HO-1 promoter, which could also be inhibited by pretreatment with a PI3K inhibitor, LY294002.ConclusionsThese results indicated that MALP-2 required TLR2/6, Btk, Mal and c-Src to activate PI3K, which in turn initiated the activation of Nrf2 for efficient HO-1 induction.

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“…T cells are felt to be functionally normal in XLA. Myeloid cells on the other hand, have had demonstrable functional deficits reported due to the role of BTK in the transduction of TLR signals [12, 13]. This has been postulated to contribute both to infection susceptibility and to a predisposition to inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

Autoimmunity and Inflammation in X-linked Agammaglobulinemia

et al. 2014

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Purpose In the past, XLA was described as associated with several inflammatory conditions, but with adequate immune globulin treatment, these are presumed to have diminished. The actual prevalence is not known. Methods A web-based patient survey was conducted December 2011- February 2012. Respondents were recruited from the Immune Deficiency Foundation (IDF) patient database, online patient discussion forums and physician recruitment of patients. The questionnaire was developed jointly by IDF and by members of the USIDNET-XLA Disease Specific Working Group. Information regarding inflammatory conditions in patients with XLA was also obtained from the United States Immune Deficiency Network (USIDNET) Registry. Results Based on 128 unique patient survey responses, the majority of respondents (69 %) reported having at least one inflammatory symptom, with 53 % reporting multiple symptoms. However, only 28 % had actually been formally diagnosed with an inflammatory condition. Although 20 % reported painful joints and 11 % reported swelling of the joints, only 7 % were given a diagnosis of arthritis. Similarly, 21 % reported symptoms of chronic diarrhea and 17 % reported abdominal pain, however only 4 % had been diagnosed with Crohn’s disease. Data from the USIDNET Registry on 149 patients with XLA, revealed that 12 % had pain, swelling or arthralgias, while 18 % had been diagnosed with arthritis. Similarly, 7 % of these patients had abdominal pain and 9 % chronic diarrhea. Conclusions Although patients with XLA are generally considered to have a low risk of autoimmune or inflammatory disease compared to other PIDD cohorts, data from this patient survey and a national registry indicate that a significant proportion of patients with XLA have symptoms that are consistent with a diagnosis of arthritis, inflammatory bowel disease or other inflammatory condition. Documented diagnoses of inflammatory diseases were less common but still increased over the general population. Additional data is required to begin implementation of careful monitoring of patients with XLA for these conditions. Early diagnosis and proper treatment may optimize clinical outcomes for these patients.

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Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia

Abstract: Our results demonstrate a predominantly inflammatory response in XLA patients after LPS stimulation and suggest a deregulation of TLR signaling in the absence of Btk. This response may be influenced by environmental factors.

Cited by 26 publications

References 27 publications

The Tec Kinase–Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages

The Tec Kinase–Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages

Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

Autoimmunity and Inflammation in X-linked Agammaglobulinemia

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