A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.

Tristetraprolin (TTP) is a widely expressed potential transcription factor that contains two unusual CCCH zinc fingers and is encoded by the immediate-early response gene, Zfp-36. Mice made deficient in TTP by gene targeting appeared normal at birth, but soon manifested marked medullary and extramedullary myeloid hyperplasia associated with cachexia, erosive arthritis, dermatitis, conjunctivitis, glomerular mesangial thickening, and high titers of anti-DNA and antinuclear antibodies. Myeloid progenitors from these mice showed no increase in sensitivity to growth factors. Treatment of young TTP-deficient mice with antibodies to tumor necrosis factor alpha (TNF alpha) prevented the development of essentially all aspects of the phenotype. These results indicate a role for TTP in regulating TNF alpha synthesis, secretion, turnover, or action. TTP-deficient mice may serve as useful models of the autoimmune inflammatory state resulting from chronic effective TNF alpha excess.

[1]  M J Thompson,et al.  Phosphorylation of Tristetraprolin, a Potential Zinc Finger Transcription Factor, by Mitogen Stimulation in Intact Cells and by Mitogen-activated Protein Kinase in Vitro(*) , 1995, The Journal of Biological Chemistry.

[2]  L. Lau,et al.  A growth factor-inducible nuclear protein with a novel cysteine/histidine repetitive sequence. , 1990, The Journal of biological chemistry.

[3]  B. Haynes,et al.  Phenotypic characterization of cutaneous T-cell lymphoma. Use of monoclonal antibodies to compare with other malignant T cells. , 1981, The New England journal of medicine.

[4]  W. Wood,et al.  Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. , 1994, Science.

[5]  D. Stumpo,et al.  Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein. , 1990, The Journal of biological chemistry.

[6]  D. Wadleigh,et al.  The Drosophila TIS11 homologue encodes a developmentally controlled gene. , 1994, Oncogene.

[7]  B. Varnum,et al.  The TIS11 primary response gene is a member of a gene family that encodes proteins with a highly conserved sequence containing an unusual Cys-His repeat , 1991, Molecular and cellular biology.

[8]  R. Eddy,et al.  The human TTP protein: sequence, alignment with related proteins, and chromosomal localization of the mouse and human genes. , 1991, Nucleic acids research.

[9]  P. Greengard,et al.  Molecular cloning, characterization, and expression of a cDNA encoding the "80- to 87-kDa" myristoylated alanine-rich C kinase substrate: a major cellular substrate for protein kinase C. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[10]  R. Kunkel,et al.  Immune Complex Vasculitis with Secondary Ulcerative Dermatitis in Aged C57BL/6NNia Mice , 1994, Veterinary pathology.

[11]  V. Sukhatme,et al.  Nucleotide sequence of a cDNA encoding TIS11, a message induced in Swiss 3T3 cells by the tumor promoter tetradecanoyl phorbol acetate. , 1989, Oncogene.

[12]  E. Robertson.  Teratocarcinomas and embryonic stem cells : a practical approach , 1987 .

[13]  M. Gomperts,et al.  The nucleotide sequence of a cDNA encoding an EGF-inducible gene indicates the existence of a new family of mitogen-induced genes. , 1990, Oncogene.

[14]  D. Pisetsky,et al.  Molecular characterization of anti-DNA antibodies induced in normal mice by immunization with bacterial DNA. Differences from spontaneous anti-DNA in the content and location of VH CDR3 arginines. , 1993, Journal of immunology.

[15]  T. Ulich,et al.  Haematologic effects of TNF. , 1993, Research in immunology.

[16]  Mario R. Capecchi,et al.  Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes , 1988, Nature.

[17]  B. Koller,et al.  Inactivating the beta 2-microglobulin locus in mouse embryonic stem cells by homologous recombination. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Kioussis,et al.  Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. , 1991, The EMBO journal.

[19]  P. Blackshear,et al.  Mitogens stimulate the rapid nuclear to cytosolic translocation of tristetraprolin, a potential zinc-finger transcription factor. , 1996, Molecular endocrinology.

[20]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[21]  R. Schreiber,et al.  Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. , 1989, Journal of immunology.

[22]  B. B. Mishell,et al.  Selected Methods in Cellular Immunology , 1980 .

[23]  A. Theofilopoulos,et al.  Murine models of systemic lupus erythematosus. , 1985, Advances in immunology.

[24]  P. Blackshear,et al.  Cloning and characterization of two yeast genes encoding members of the CCCH class of zinc finger proteins: zinc finger-mediated impairment of cell growth. , 1996, Gene.

[25]  H. Broxmeyer,et al.  Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1 alpha. , 1994, Experimental hematology.