Abstract
Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling.
Highlights
Tumour necrosis factor (TNF) production is precisely regulated at both the gene and protein expression level [1]
An increase in Bruton's Tyrosine Kinase (Btk) phosphorylation occurred within 10mins of R848 (TLR7/8) stimulation (Fig. 1B)
Overexpression of Btk resulted in significantly increased TNF production in response to both LPS and R848 (Fig. 1D and E)
Summary
TNF production is precisely regulated at both the gene and protein expression level [1]. Toll-like receptors (TLRs), by recognising ligands as diverse as bacterial cell wall components and nucleic acids, are important inducers of TNF production in disease. Non-receptor tyrosine kinases play a major role in TLR signalling [3e5], and in particular, Bruton's Tyrosine Kinase (Btk), a member of the Tec family of non-receptor protein tyrosine kinases (PTKs), is a crucial regulator of TLR induced TNF production [6,7]. A lack of functional Btk leads to X-linked agammaglobulinemia (XLA), a condition characterised by both B cell deficiency and ineffective immune responses to bacterial and viral challenge [8]. Btk deficiency in B cells reduces TLR9-induced production of IL-10, leading to elevated levels of TNF, IL-6 and IL-12p40 [12,13] a finding that may explain the increased levels of cytokines present in XLA serum [14]
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