p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC-and FANCA-deficient mononuclear phagocytes
p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC-and FANCA-deficient mononuclear phagocytes
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DOI：
10.1182/blood-2011-06-354647
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发表时间：
2012-03-01
期刊：
影响因子：
20.3
通讯作者：
Bagby, Grover C.
中科院分区：
文献类型：
--
作者：
Anur, Praveen;Yates, Jane;Bagby, Grover C.
Fanconi贫血、互补组C（FANCC）缺陷型造血干细胞和祖细胞对多种抑制性细胞因子高度敏感，其中之一TNF α可在FANCC缺陷型小鼠中诱导BM衰竭和克隆进化。FANCC缺陷型巨噬细胞也对TLR活化高度敏感，并以不受限制的方式产生TNF α。由于抑制性细胞因子的产生可能会增强造血，我们使用TLR激动剂刺激的FANCC和Fanconi贫血，含有NF-κ B/AP-1应答报告基因（SEAP）的A型互补组（FANCA）缺陷型巨噬细胞筛选小分子。在筛选的75种小分子中，p38 MAPK抑制剂BIRB 796和达沙替尼有效抑制了报告基因的TLR 8依赖性表达。范可尼贫血（FA）巨噬细胞对TLR 7/8激活剂R848超敏，响应于所有剂量的激动剂而过度产生SEAP和TNF α。低剂量（50 nM）的两种药物均抑制MAPKAPK 2（MK2）的p38 MAPK依赖性活化，并抑制MK2依赖性TNF α产生，而基本上不影响TNF α基因转录。原代FA细胞过度产生TNF α同样受到这些药物的抑制，并涉及MK2活化的抑制。由于MK2也已知影响FA造血祖细胞特别易受的2种其他抑制因子（MIP-1 α和IFN γ）的产生和/或敏感性，因此在FA造血细胞中靶向p38 MAPK是临床前评价的合理目标。（血。2012; 119（9）：1992-2002）
Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNF alpha, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNF alpha in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist-stimulated FANCC-and Fanconi anemia, complementation group A (FANCA)-deficient macrophages containing an NF-kappa B/AP-1-responsive reporter gene (SEAP). Of the 75 small molecules screened, the p38 MAPK inhibitor BIRB 796 and dasatinib potently suppressed TLR8-dependent expression of the reporter gene. Fanconi anemia (FA) macrophages were hypersensitive to the TLR7/8 activator R848, overproducing SEAP and TNF alpha in response to all doses of the agonist. Low doses (50nM) of both agents inhibited p38 MAPK-dependent activation of MAPKAPK2 (MK2) and suppressed MK2-dependent TNF alpha production without substantially influencing TNF alpha gene transcription. Overproduction of TNF alpha by primary FA cells was likewise suppressed by these agents and involved inhibition of MK2 activation. Because MK2 is also known to influence production and/or sensitivity to 2 other suppressive factors (MIP-1 alpha and IFN gamma) to which FA hematopoietic progenitor cells are uniquely vulnerable, targeting of p38 MAPK in FA hematopoietic cells is a rational objective for preclinical evaluation. (Blood. 2012; 119(9): 1992-2002)