A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response.
Ricin activates the proinflammatory ribotoxic stress response through the mitogen activated protein 3 kinase (MAP3K) ZAK, resulting in activation of mitogen activated protein kinases (MAPKs) p38 and JNK1/2. We had a novel zak-/- mouse generated to study the role of ZAK signaling in vivo during ricin intoxication. To characterize this murine strain, we intoxicated zak-/- and zak+/+ bone marrow-derived murine macrophages with ricin, measured p38 and JNK1/2 activation by Western blot, and measured zak, c-jun, and cxcl-1 expression by qRT-PCR. To determine whether zak-/- mice differed from wild-type mice in their in vivo response to ricin, we performed oral ricin intoxication experiments with zak+/+ and zak-/- mice, using blinded histopathology scoring of duodenal tissue sections to determine differences in tissue damage. Unlike macrophages derived from zak+/+ mice, those derived from the novel zak-/- strain fail to activate p38 and JNK1/2 and have decreased c-jun and cxcl-1 expression following ricin intoxication. Furthermore, compared with zak+/+ mice, zak-/- mice have decreased duodenal damage following in vivo ricin challenge. zak-/- mice demonstrate a distinct ribotoxic stress-associated phenotype in response to ricin and therefore provide a new animal model for in vivo studies of ZAK signaling.
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA. dakshina.jandhyala@tufts.edu.|Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA 02111, USA. dakshina.jandhyala@tufts.edu.
Dakshina M
DM
Jandhyala
School of Nursing, MGH Institute of Health Professions, Boston, MA 02129, USA. jwong1@mghihp.edu.
John
J
Wong
Division of Infectious Disease, Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA. nicholas.mantis@health.ny.gov.
Nicholas J
NJ
Mantis
School of Nursing, MGH Institute of Health Professions, Boston, MA 02129, USA. bmagun@mghihp.edu.
Bruce E
BE
Magun
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA. john.leong@tufts.edu.
John M
JM
Leong
Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA 02111, USA. cthorpe@tuftsmedicalcenter.org.
Cheleste M
CM
Thorpe
D000818:Animals; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D004386:Duodenum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005838:Genotype; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012276:Ricin / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D054360:Chemokine CXCL1; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D016755:Proto-Oncogene Proteins c-jun; D012276:Ricin; D048051:p38 Mitogen-Activated Protein Kinases; C475895:Cxcl1 protein, mouse; C581706:Map3k20 protein, mouse
JNK1/2; MAP3K; Ribotoxic Stress Response; Ricin; ZAK; inflammation; macrophage; murine; p38; protein synthesis inhibition