Tyrphostin A1

Tyrphostin A1(AG9) inhibits CD40L-stimulated IL-12 production in macrophage cultures and antigen-induced generation of Th1 cells. IC50 value: Target: IL-12 production inhibitor Addition of increasing concentration of A1 resulted in a dose dependent decrease of IL-12 p40, with maximal inhibition (62.5%) occurring at a dose of 10 μM. tyrphostin A1 blocks CD40L-induced translocation of NF-κB to the nucleus, and reduces the activation of IL-12 p40 gene. In vivo therapy with A1 leads to decrease in generation of myelin basic protein (MBP) specific encephalitogenic T cells. In addition, treatment of SJL/J mice with A1 results in attenuation of experimental allergic encephalomyelitis (EAE) [1]. Tyrphostin A1 is a much weaker inhibitor of TK than other tyrphostins (IC50>1250 μM for epidermal growth factor receptor (EGFR) kinase), and therefore often used to differentiate TK-mediated effects of tyrphostins from other non-specific effects [2].

References:
[1]. Du C, et al. Inhibition of CD40 signaling pathway by tyrphostin A1 reduces secretion of IL-12 in macrophage, Th1 cell development and experimental allergic encephalomyelitis in SJL/J mice. J Neuroimmunol. 2001 Mar 1;114(1-2):69-79. [2]. Ogura T, et al. Activation of background membrane conductance by the tyrosine kinase inhibitor tyrphostin A23 and its inactive analog tyrphostin A1 in guinea pig ventricular myocytes. Jpn J Pharmacol. 2001 Nov;87(3):235-9.

Activation of background membrane conductance by the tyrosine kinase inhibitor tyrphostin A23 and its inactive analog tyrphostin A1 in guinea pig ventricular myocytes.[Pubmed:11885974]

Jpn J Pharmacol. 2001 Nov;87(3):235-9.

ABSTRACT-The effects of the tyrosine kinase (TK) inhibitor tyrphostin A23 and its inactive analog tyrphostin Al on background membrane conductance were investigated in guinea pig ventricular myocytes. TK-inhibiting A23 reversibly increased membrane conductance under conditions designed to minimize Na+, Ca2+, K+, and Na+-K+ pump currents. Similar stimulatory action was obtained with TK-inactive Al. The tyrphostin-induced current was inhibited by omitting external Na+ or Ca+, suppressed by chelating internal Ca2+, blocked by external Cd2+ and Ni2+, and insensitive to changes in internal Cl- concentration. We conclude that tyrphostins have a direct, TK-independent action that increases membrane conductance probably by stimulating Na+-Ca2+ exchange.

Inhibition of CD40 signaling pathway by tyrphostin A1 reduces secretion of IL-12 in macrophage, Th1 cell development and experimental allergic encephalomyelitis in SJL/J mice.[Pubmed:11240017]

J Neuroimmunol. 2001 Mar 1;114(1-2):69-79.

Activation of antigen presenting cells through the interaction of CD40 with its ligand is a critical co-stimulatory signal for IL-12 production and Th1 differentiation. Tyrphostins are organic molecules that inhibit the phosphorylation of protein tyrosine kinases. We show that Tyrphostin A1 inhibits CD40L-stimulated IL-12 production in macrophage cultures and antigen-induced generation of Th1 cells. Our data also show that Tyrphostin A1 blocks CD40L-induced translocation of NF-kappaB to the nucleus, and reduces the activation of IL-12 p40 gene. In vivo therapy with A1 leads to decrease in generation of myelin basic protein (MBP) specific encephalitogenic T cells. In addition, treatment of SJL/J mice with A1 results in attenuation of experimental allergic encephalomyelitis (EAE).

Tyrphostin A1(AG9) inhibits CD40L-stimulated IL-12 production in macrophage cultures and antigen-induced generation of Th1 cells.

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