ABSTRACT
Both IL-4 and IL-10 have been shown in vitro to inhibit leukemia cell secretion of IL-1beta, GM-CSF, and TNFalpha, and increase leukemia cell release of IL-1ra. In this study, we have investigated the in vivo effects of IL-4, IL-10, and amifostine on cytokine production in patients with acute myelogenous leukemia (AML). Serum IL-1ra, IL-1beta, TNFalpha, GM-CSF, and SCF levels were measured in AML patients who received IL-4, IL-10, or amifostine. No significant changes in the serum levels of IL-1ra, IL-1beta, TNFalpha, GM-CSF, and SCF were found in AML patients who received amifostine. Both IL-4 and IL-10 were found to increase serum IL-1ra. This data is in accord with the in vitro studies. However, IL-4 increased serum GM-CSF levels and IL-10 increased serum IL-1beta and TNFalpha levels. These in vivo effects of the two cytokines differ from their in vitro effects. Despite the similar effects of IL-4 and IL-10 on cytokine production by AML cells in vitro, different effects were observed in AML patients in vivo. IL-4 increased serum SCF levels, whereas IL-10 decreased serum SCF levels. IL-4 increased serum GM-CSF levels, whereas IL-10 had no effect on them. Although IL-10 increased serum IL-1beta and TNFalpha levels, IL-4 had no effect on them. These findings indicate that the in vitro effects of IL-4 and IL-10 do not necessarily reflect their in vivo effects, and that the complex effects of the two cytokines on serum cytokine levels make it difficult to predict their therapeutic potential.
Subject(s)
Amifostine/administration & dosage , Cytokines/biosynthesis , Interleukin-10/administration & dosage , Interleukin-4/administration & dosage , Amifostine/pharmacology , Cytokines/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Granulocyte-Macrophage Colony-Stimulating Factor/drug effects , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-1/blood , Interleukin-10/pharmacology , Interleukin-4/pharmacology , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Radiation-Protective Agents/administration & dosage , Radiation-Protective Agents/pharmacology , Sialoglycoproteins/blood , Sialoglycoproteins/drug effects , Stem Cell Factor/blood , Stem Cell Factor/drug effects , Time Factors , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Molecular species of the Na(+)-H(+) exchanger (NHE) and anion exchanger (AE) gene families and their relative abundance in the human airway regions were assessed utilizing RT-PCR and the RNase protection assay, respectively. Organ donor lung epithelia from various bronchial regions (small, medium, and large bronchi and trachea) were harvested for RNA extraction. Gene-specific primers for the human NHE and AE isoforms were utilized for RT-PCR. Our results demonstrated that NHE1, AE2, and brain AE3 isoforms were expressed in all regions of the human airway, whereas NHE2, NHE3, AE1, and cardiac AE3 were not detected. RNase protection studies for NHE1 and AE2, utilizing glyceraldehyde-3-phosphate dehydrogenase as an internal standard, demonstrated that there were regional differences in the NHE1 mRNA levels in human airways. In contrast, the levels of AE2 mRNA remained unchanged. Differential regional expression of NHE1 isoform may be related to a higher acid load in the tracheal epithelial cells than in epithelia of distal airways. Fluctuations in PCO(2) during inspiration and expiration are probably larger in the tracheal lumen than in the lumen of distal airways with associated larger swings in intracellular pH with each respiratory cycle. Immunohistochemical staining for AE2 protein demonstrated localization to the epithelial cells of human bronchial mucosa.
Subject(s)
Chloride-Bicarbonate Antiporters/analysis , Respiratory Mucosa/chemistry , Sodium-Hydrogen Exchangers/analysis , Bronchi/chemistry , Bronchi/metabolism , Chloride-Bicarbonate Antiporters/biosynthesis , Chloride-Bicarbonate Antiporters/genetics , DNA/genetics , DNA Footprinting , Female , Humans , Immunohistochemistry , Male , Middle Aged , Respiratory Mucosa/metabolism , Sodium-Hydrogen Exchangers/biosynthesis , Sodium-Hydrogen Exchangers/genetics , Trachea/chemistry , Trachea/metabolismABSTRACT
Recent studies have indicated the presence of Na+/H+ and Cl-/HCO-3 exchange activities in lung alveolar and tracheal tissues of various species. To date, the identity of the Na+/H+ (NHE) and Cl-/HCO-3 (AE) exchanger isoforms and their regional distribution in human airways are not known. Molecular species of the NHE and AE gene families and their relative abundance in the human airway regions were assessed utilizing RT-PCR and the RNase protection assay, respectively. Organ donor lung epithelia from various bronchial regions (small, medium, and large bronchi and trachea) were harvested for RNA extraction. Gene-specific primers for the human NHE and AE isoforms were utilized for RT-PCR. Our results demonstrated that NHE1, AE2, and brain AE3 isoforms were expressed in all regions of the human airways, whereas NHE2, NHE3, AE1, and cardiac AE3 were not detected. RNase protection studies for NHE1 and AE2, utilizing glyceraldehyde-3-phosphate dehydrogenase as an internal standard, demonstrated that there were regional differences in the NHE1 mRNA levels in human airways. In contrast, the levels of AE2 mRNA remained unchanged. Differential expression of these isoforms in the human airways may have functional significance related to the airway absorption and secretion of electrolytes.
