Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes

被引:33
作者
Bhattacharjee, Ashish [1 ,2 ]
Pal, Srabani [1 ,2 ]
Feldman, Gerald M. [3 ]
Cathcart, Martha K. [1 ,2 ]
机构
[1] Cleveland Clin, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44195 USA
[2] Case Western Reserve Univ, Lerner Coll Med, Dept Mol Med, Cleveland Clin, Cleveland, OH 44195 USA
[3] US FDA, Div Monoclonal Antibodies, Off Therapeut Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
SMOOTH-MUSCLE-CELLS; KINASE-C-DELTA; HUMAN ATHEROSCLEROTIC PLAQUES; CENTRIFUGAL ELUTRIATION CCE; SIGNAL-TRANSDUCTION PATHWAY; PERIPHERAL-BLOOD MONOCYTES; POLAR STEROL ESTERS; SRC-FAMILY KINASES; NF-KAPPA-B; PROTEIN-KINASE;
D O I
10.1074/jbc.M111.291492
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
IL-13 is a Th2 cytokine that promotes alternative activation (M2 polarization) in primary human monocytes. Our studies have characterized the functional IL-13 receptor complex and the downstream signaling events in response to IL-13 stimulation in alternatively activated monocytes/macrophages. In this report, we present evidence that IL-13 induces the activation of a Src family tyrosine kinase, which is required for IL-13 induction of M2 gene expression, including 15-lipoxygenase (15-LO). Our data show that Src kinase activity regulates IL-13-induced p38 MAPK tyrosine phosphorylation via the upstream kinases MKK3or MKK6. Our findings also reveal that the IL-13 receptor-associated tyrosine kinase Jak2 is required for the activation of both Src kinase as well as p38 MAPK. Further, we found that Src tyrosine kinase-mediated activation of p38 MAPK is required for Stat1 and Stat3 serine 727 phosphorylation in alternatively activated monocytes/macrophages. Additional studies identify Hck as the specific Src family member, stimulated by IL-13 and involved in regulating both p38 MAPK activation and p38 MAPK-mediated 15-LO expression. Finally we show that the Hck regulates the expression of other alternative state (M2)-specific genes (Mannose receptor, MAO-A, and CD36) and therefore conclude that Hck acts as a key regulator controlling gene expression in alternatively activated monocytes/macrophages.
引用
收藏
页码:36709 / 36723
页数:15
相关论文
共 71 条
[1]   Role of PKCs and NF-κB activation in myocardial inflammation:: Enemy or ally? [J].
Abe, Jun-ichi .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2007, 43 (04) :404-408
[2]   MAP kinases differentially regulate the expression of macrophage hyperactivity after thermal injury [J].
Alexander, M ;
Daniel, T ;
Chaudry, IH ;
Schwacha, MG .
JOURNAL OF CELLULAR PHYSIOLOGY, 2004, 201 (01) :35-44
[3]   Modulation of PKCδ tyrosine phosphorylation and activity in salivary and PC-12 cells by Src kinases [J].
Benes, C ;
Soltoff, SP .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2001, 280 (06) :C1498-C1510
[4]   IL-13 induces expression of CD36 in human monocytes through PPARγ activation [J].
Berry, Antoine ;
Balard, Patricia ;
Coste, Agnes ;
Olagnier, David ;
Laganel, Celine ;
Authier, Helene ;
Benoit-Vical, Francoise ;
Lepert, Jean-Claude ;
Seguela, Jean-Paul ;
Magnaval, Jean-Francois ;
Chambon, Pierre ;
Metzger, Daniel ;
Desvergne, Beatrice ;
Wahli, Walter ;
Auwerx, Johan ;
Pipy, Bernard .
EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (06) :1642-1652
[5]   Monocyte 15-lipoxygenase expression is regulated by a novel cytosolic signaling complex with protein kinase C δ and tyrosine-phosphorylated Stat3 [J].
Bhattacharjee, Ashish ;
Xu, Bo ;
Frank, David A. ;
Feldman, Gerald M. ;
Cathcart, Martha K. .
JOURNAL OF IMMUNOLOGY, 2006, 177 (06) :3771-3781
[6]   Monocyte 15-Lipoxygenase Gene Expression Requires ERK1/2 MAPK Activity [J].
Bhattacharjee, Ashish ;
Mulya, Anny ;
Pal, Srabani ;
Roy, Biswajit ;
Feldman, Gerald M. ;
Cathcart, Martha K. .
JOURNAL OF IMMUNOLOGY, 2010, 185 (09) :5211-5224
[7]   Integrin β3-mediated Src activation regulates apoptosis in IEC-6 cells via Akt and STAT3 [J].
Bhattacharya, Sujoy ;
Ray, Ramesh M. ;
Johnson, Leonard R. .
BIOCHEMICAL JOURNAL, 2006, 397 (03) :437-447
[8]   IL-2 signaling in human monocytes involves the phosphorylation and activation of p59hck [J].
Bosco, MC ;
Curiel, RE ;
Zea, AH ;
Malabarba, MG ;
Ortaldo, JR ;
Espinoza-Delgado, I .
JOURNAL OF IMMUNOLOGY, 2000, 164 (09) :4575-4585
[9]  
BOULET I, 1992, ONCOGENE, V7, P703
[10]   LIPIDS OF HUMAN ATHEROMA .4. CHARACTERISATION OF A NEW GROUP OF POLAR STEROL ESTERS FROM HUMAN ATHEROSCLEROTIC PLAQUES [J].
BROOKS, CJW ;
STEEL, G ;
GILBERT, JD ;
HARLAND, WA .
ATHEROSCLEROSIS, 1971, 13 (02) :223-&