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1.
J Immunol ; 165(4): 2214-21, 2000 Aug 15.
Article in English | MEDLINE | ID: mdl-10925309

ABSTRACT

Cytokines produced by activated macrophages and Th2 cells within the lung play a key role in asthma-associated airway inflammation. Additionally, recent studies suggest that the molecule CD40 modulates lung immune responses. Because airway epithelial cells can act as immune effector cells through the expression of inflammatory mediators, the epithelium is now considered important in the generation of asthma-associated inflammation. Therefore, the goal of the present study was to examine the effects of proinflammatory and Th2-derived cytokines on the function of CD40 in airway epithelia. The results show that airway epithelial cells express CD40 and that engagement of epithelial CD40 induces a significant increase in expression of the chemokines RANTES, monocyte chemoattractant protein (MCP-1), and IL-8 and the adhesion molecule ICAM-1. Cross-linking epithelial CD40 had no effect on expression of the adhesion molecule VCAM-1. The proinflammatory cytokines TNF-alpha and IL-1beta and the Th2-derived cytokines IL-4 and IL-13 modulated the positive effects of CD40 engagement on inflammatory mediator expression in airway epithelial cells. Importantly, CD40 ligation enhanced the sensitivity of airway epithelial cells to the effects of TNF-alpha and/or IL-1beta on expression of RANTES, MCP-1, IL-8, and VCAM-1. In contrast, neither IL-4 nor IL-13 modified the effects of CD40 engagement on the expression of RANTES, MCP-1, IL-8, or VCAM-1; however, both IL-4 and IL-13 attenuated the effects of CD40 cross-linking on ICAM-1 expression. Together, these findings suggest that interactions between CD40-responsive airway epithelial cells and CD40 ligand+ leukocytes, such as activated T cells, eosinophils, and mast cells, modulate asthma-associated airway inflammation.


Subject(s)
Adjuvants, Immunologic/physiology , Bronchi/immunology , Bronchi/pathology , CD40 Antigens/physiology , Cytokines/physiology , Inflammation Mediators/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Animals , Bronchi/metabolism , CD40 Antigens/biosynthesis , Cell Adhesion Molecules/biosynthesis , Cell Line , Chemokines/biosynthesis , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelium/immunology , Epithelium/metabolism , Epithelium/pathology , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation Mediators/immunology , Membrane Proteins/biosynthesis , Mice , Mice, Inbred BALB C
2.
Am J Physiol ; 276(3): C700-10, 1999 03.
Article in English | MEDLINE | ID: mdl-10069998

ABSTRACT

To delineate the mechanisms that facilitate leukocyte migration into the cystic fibrosis (CF) lung, expression of chemokines, including interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and RANTES, was compared between CF and non-CF airway epithelia. The findings presented herein demonstrate that, under either basal conditions or tumor necrosis factor-alpha (TNF-alpha)- and/or interferon-gamma (IFN-gamma)-stimulated conditions, a consistent pattern of differences in the secretion of IL-8 and MCP-1 between CF and non-CF epithelial cells was not observed. In contrast, CF epithelial cells expressed no detectable RANTES protein or mRNA under basal conditions or when stimulated with TNF-alpha and/or IFN-gamma (P

Subject(s)
Bronchi/metabolism , Chemokine CCL5/metabolism , Chemokines/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/physiology , Cystic Fibrosis/metabolism , Bronchi/drug effects , Bronchi/pathology , Chemokine CCL2/metabolism , Chemokine CCL5/genetics , Drug Combinations , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Interferon-gamma/pharmacology , Interleukin-8/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Promoter Regions, Genetic/physiology , RNA, Messenger/metabolism , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/pharmacology
3.
J Biol Chem ; 273(1): 361-8, 1998 Jan 02.
Article in English | MEDLINE | ID: mdl-9417089

ABSTRACT

Suppressin (SPN) is an inhibitor of cell proliferation that was originally identified and purified to homogeneity from bovine pituitaries (LeBoeuf, R. D., Burns, J. N., Bost, K. L., and Blalock, J. E. (1990) J. Biol. Chem. 265, 158-165). In this report we have cloned the full-length cDNA encoding rat SPN and have identified the tissue distribution of SPN expression. The cDNA of SPN is 1882 nucleotides with a 1488-base coding region and 55 and 339 nucleotides of 5'- and 3'-untranslated sequences, respectively. Northern gel analysis of rat pituitary mRNA showed a single hybridizing species at approximately 2 kilobases. Sequence analyses showed that the nucleotide and deduced amino acid sequences of SPN are novel and unrelated to any known vertebrate inhibitors of proliferation. However, the deduced amino acid sequence of SPN contains two domains that have extensive sequence identity with a recently cloned transcription activator in Drosophila, deformed epidermal autoregulatory factor-1 (DEAF-1, see Gross, C. T., and McGinnis, W. (1996) EMBO J. 15, 1961-1970) suggesting that SPN represents a vertebrate cognate of deformed epidermal autoregulatory factor-1. Reverse transcriptase-polymerase chain reaction and immunohistochemical analyses showed that the SPN mRNA and the SPN protein are expressed in every tissue examined including testis, spleen, skeletal muscle, liver, kidney, heart, and brain suggesting that SPN may be involved in the control of proliferation in a variety of cell types.


Subject(s)
Cell Cycle , Thymus Hormones/genetics , Amino Acid Sequence , Animals , Base Sequence , Cattle , Cloning, Molecular , DNA, Complementary , Male , Molecular Sequence Data , Pituitary Gland/cytology , Pituitary Gland/metabolism , Rats , Rats, Sprague-Dawley , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Structure-Activity Relationship , Thymus Hormones/chemistry , Thymus Hormones/metabolism
4.
Endocrinology ; 133(1): 241-7, 1993 Jul.
Article in English | MEDLINE | ID: mdl-8319573

ABSTRACT

Suppressin (SPN) is a novel polypeptide that is synthesized and secreted by normal rat pituitary cells and a rat pituitary tumor cell line, GH3. Specifically, SPN is a negative regulator of growth that inhibits lymphoid and neuroendocrine cell proliferation. The objective of the present study was to identify the cells in the normal rat pituitary that produce SPN. A double immunofluorescence technique, using antibodies to SPN in conjunction with antibodies to the six major adenohypophyseal hormones, was used to colocalize SPN and a specific hormone in a single dispersed pituitary cell. The results of these experiments showed that, on the average, 42% of the cells in the pituitary produce SPN. Suppressin production in the pituitary was restricted to the adenohypophysis. The SPN-producing population in the pituitary was composed of somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and mammosomatotrophs, while gonadotrophs did not produce SPN. Additionally, a PRL reverse hemolytic plaque assay was used to examine SPN production in lactotrophs. The results of these experiments showed that SPN production and the amount of PRL secreted covaried. Specifically, SPN production was observed primarily in non-PRL-secreting lactotrophs or in lactotrophs secreting a high amount of PRL. The results of these experiments suggest a potential regulatory relationship between the synthesis and secretion of SPN and PRL. In summary, this report provides the first identification of SPN-producing cells in the pituitary and shows that SPN production occurs primarily in somatotrophs and lactotrophs.


Subject(s)
Pituitary Gland/cytology , Pituitary Gland/metabolism , Thymus Hormones/biosynthesis , Animals , Antibodies, Monoclonal , Cell Count , Fluorescent Antibody Technique , Hemolytic Plaque Technique , Male , Phenotype , Pituitary Gland, Anterior/cytology , Pituitary Gland, Anterior/metabolism , Prolactin/metabolism , Rats
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