Macrophage Effector Functions Controlled by Bruton’s Tyrosine Kinase Are More Crucial Than the Cytokine Balance of T Cell Responses for Microfilarial Clearance

265

249

The Tec family of protein tyrosine kinases, of which Bruton's tyrosine kinase (Btk) 1 is a prototypical member, is involved in a vast array of signaling pathways in cells of hematopoietic lineage. Btk is expressed in all hematopoietic cells except T lymphocytes and natural killer cells. It is critically important for B-cell development as well as mature B-cell activation and survival. It has also been shown to be important for IgEmediated activation of mast cells resulting in allergic reactions. Btk kinase activity and tyrosine phosphorylation have both been shown to increase upon cross-linking or stimulation of the B-cell receptor, the IgE receptor (Fc⑀RII), and a number of cytokine receptors such as those for IL-3, IL-5, IL-6, and IL-10, suggesting a general role for Btk in immune regulation (1-4). Whereas the molecular mechanisms by which the B-cell receptor regulates B-cell proliferation and survival are not well understood, Btk has recently been shown to lie downstream of the B-cell receptor on the pathway regulating activation of the key pro-inflammatory transcription factor NF B (5-8). The biological importance of the signaling function has been shown by naturally occurring loss of function mutations in Btk in human X-linked agammaglobulinemia and its murine counterpart, X-linked immunodeficiency (Xid). These diseases are characterized by a block in B-cell development and defects in B-cell signaling, and in X-linked agammaglobulinemia patients, mutations in Btk are associated associated with an increased frequency of bacterial infections in all organs (9). Studies in Xid mice have also shown reduced responses to LPS stimulation, with nitric oxide (NO) production decreased, and macrophage effector functions impaired (10 -12). This, coupled with the observation that responses to T-independent antigens are impaired in Xid mice, suggests a role for Btk in innate immune responses.Toll-like receptors (TLRs) have an essential function in both innate and adaptive immunity and have evolved to recognize, with high specificity, diverse microbial pathogens (13). TLR4, as the receptor for the Gram-negative bacterial product LPS, is the prototypical member of the family (numbered TLR1-10 in humans) of type I transmembrane receptors, which are characterized by an extracellular leucine-rich repeat domain and an intracellular Toll/IL-1 receptor (TIR) domain, responsible for signaling. Ligands for other family members (except TLR10) have been identified and include bacterial flagellin and unmethylated bacterial CpG motifs for TLR5 and TLR9, respectively; double-stranded RNA for TLR3; and the antiviral compound R-848 recognizing TLR7 and TLR8. Research into how these receptors signal has identified MyD88 and IL-1-receptorassociated kinases (IRAKs) as key proximal signaling components regulating activation of the pro-inflammatory transcription factor NF B in response to LPS (reviewed in Ref. 14). Important differences in the proteins recruited to the different TLR members have also been described. Both TLR2 (the receptor for...

Section: Discussionmentioning

confidence: 96%

Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4

Jefferies

Doyle

Brunner

et al. 2003

265

249

“…The mice were injected intraperitoneally with 1 ml of 4% sterile thioglycolate broth, and after 3 days, peritoneal macrophages were isolated as described earlier (35,36). The animal experiments were conducted at the National Institute of Nutrition, Hyderabad, India, upon approval by the Institutional Animal Ethics Committee of the National Institute of Nutrition, Hyderabad, India.…”

Section: Methodsmentioning

confidence: 99%

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

Parveen

Varman

Nair

et al. 2013

Self Cite

Background: Mtbhsp60 induces TLR2-mediated anti-inflammatory response in macrophages, but the mechanisms are not well understood. Results: Clathrin-dependent TLR2-mediated endocytosis of Mtbhsp60 is required to induce anti-inflammatory response via p38 MAPK activation. Conclusion: Mtbhsp60 induces anti-inflammatory response upon endocytosis. Blockage of endocytosis predominantly leads to pro-inflammatory cytokine production. Significance: This information is important to tailor the Mtbhsp60-triggered IL-10 signaling to specifically block the excess nonprotective Th2-type response.

“…However, several studies have provided a more general role for Btk in immune regulation. Studies in Xid peritoneal macrophages have shown reduced responses to lipopolysaccharide (LPS) stimulation, with tumor necrosis factor ␣ (TNF␣) and IL-1␤ production decreased and macrophage effector functions impaired (5). We have shown that Btk is recruited to the LPS receptor Toll-like receptor-4 (TLR4) where it is activated and is required for NFB activation (6).…”

mentioning

confidence: 99%

Bruton's Tyrosine Kinase Is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFκB Activation by Lipopolysaccharide

Doyle

Jefferies²,

O’Neill³

2005

131

102

Bruton's tyrosine kinase (Btk) has recently been shown to participate in the induction of nuclear factor B (NFB)-dependent gene expression by the lipopolysaccharide (LPS) receptor Toll-like receptor-4 (TLR4). In this study we have examined the mechanism whereby Btk participates in this response. Treatment of the murine monocytic cell line Raw264.7 with LFM-A13, a specific Btk inhibitor, blocked LPS-induced NFB-dependent reporter gene expression but not IB␣ degradation. Transient transfection of HEK293 cells with Btk had no effect on NFB-dependent reporter gene expression but strongly promoted transactivation of a reporter gene by a p65-Gal4 fusion protein. IB␣ degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk. Transfection of cells with a dominant negative form of Btk (BtkK430R) inhibited LPS-driven p65 mediated transactivation. Additionally LFM-A13 impaired phosphorylation of serine 536 on p65 induced by LPS in HEK293-TLR4 cells, and in Xid macrophages this response was impaired. This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFB.Bruton's tyrosine kinase (Btk) 1 is a member of the Tec family of non-receptor tyrosine kinases and is found in all cells of the hematopoietic lineage except plasma cells and T-cells (1). In B-cells, activation of the B-cell receptor leads to Btk being rapidly recruited to the plasma membrane where it becomes phosphorylated and activated. Btk is required for normal B-cell development (2) and the gene encoding Btk was first identified as the mutated gene in X-linked agammaglobulinemia (XLA) in humans, an immune disease characterized by a lack of circulating B lymphocytes and an absence of Igs of all classes (3). Mutations in the Btk gene also result in the less severe Xlinked immunodeficiency (Xid) in mice. Various mutations have been identified as being responsible for the XLA phenotype, whereas the mutation in Xid mice has been mapped to arginine 28 (R28C) in the PH domain (4). This prevents Btk associating with the membrane, thus inactivating it. The PH domain is important in the process of Btk activation, since it localizes Btk to the membrane through its interaction with phosphatidylinositol triphosphate (PIP 3 ), which is generated by phosphatidylinositol 3-kinase (PI3K).Due to the major phenotype of Btk deficiency being impaired B-cell development and function, the main focus of interest in Btk has centered around the B-cell. However, several studies have provided a more general role for Btk in immune regulation. Studies in Xid peritoneal macrophages have shown reduced responses to lipopolysaccharide (LPS) stimulation, with tumor necrosis factor ␣ (TNF␣) and IL-1␤ production decreased and macrophage effector functions impaired (5). We have shown that Btk is recruited to the LPS receptor Toll-like receptor-4 (TLR4) where it is activated and is required f...