A Novel Zak Knockout Mouse with a Defective Ribotoxic Stress Response

• Published in: Toxins Vol. 8; no. 9; p. 259
• Main Authors: Jandhyala, Dakshina M, Wong, John, Mantis, Nicholas J, Magun, Bruce E, Leong, John M, Thorpe, Cheleste M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 02.09.2016; MDPI AG
• Subjects: Animals; Cells, Cultured; Chemokine CXCL1 - metabolism; Communication; Duodenum - drug effects; Duodenum - enzymology; Duodenum - pathology; Enzyme Activation; Genotype; inflammation; JNK Mitogen-Activated Protein Kinases - metabolism; JNK1/2; macrophage; Macrophages - drug effects; Macrophages - enzymology; Macrophages - pathology; MAP Kinase Kinase Kinases - deficiency; MAP Kinase Kinase Kinases - genetics; MAP3K; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; murine; p38; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; protein synthesis inhibition; Proto-Oncogene Proteins c-jun - metabolism; Ribotoxic Stress Response; Ricin; Ricin - toxicity; Signal Transduction - drug effects; Stress, Physiological - drug effects; ZAK; murine; p38; Ricin; ZAK; inflammation; JNK1/2; macrophage; Ribotoxic Stress Response; protein synthesis inhibition; MAP3K
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins8090259

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.