Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor.
Accumulating evidence supports the hypothesis that neuroendocrine hormones may participate in immunologic processes. In our study we have determined that UK-14304 (UK) and norepinephrine (NE), both alpha 2-adrenergic agonists, can augment LPS-stimulated TNF from elicited macrophages (MO). The increase in TNF production was concentration dependent with an EC50 for UK and NE of 8.1 +/- 2.6 and 0.52 +/- 0.17 nM, respectively. The concentration-effect curve for UK and NE was shifted to the right by the alpha 2-antagonist yohimbine (10(-6) M), with new EC50 of 49.7 +/- 12.2 (p less than 0.001) nM and 10.3 +/- 22 nM. The augmenting effect of UK on MO TNF production was assessed over a 7 log LPS response curve. Within a single population of MO 10 nM UK shifted the LPS-induced TNF curve eightfold to the left with the greatest increase in TNF production at lower LPS concentrations. At the transcriptional level, Northern blot analysis demonstrated that UK increased LPS-induced TNF mRNA accumulation. This augmentation in TNF mRNA accumulation was blocked by yohimbine. The presence of a MO alpha-adrenergic receptor was established by demonstrating binding of the alpha 2-adrenergic antagonist 3H-yohimbine to membranes prepared from MO. This binding was rapid, saturable, reversible, and blocked by UK, clonidine, and phentolamine. These investigations support the role of alpha 2 adrenergic agonists as immunostaining compounds that may regulate cytokine production during an inflammatory response.
Spengler
R N
RN
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Allen
R M
RM
Remick
D G
DG
Strieter
R M
RM
Kunkel
S L
SL
D000818:Animals; D001483:Base Sequence; D000068438:Brimonidine Tartrate; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009638:Norepinephrine / Q000494:pharmacology; D015345:Oligonucleotide Probes; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D015016:Yohimbine / Q000494:pharmacology
D008070:Lipopolysaccharides; D015345:Oligonucleotide Probes; D011810:Quinoxalines; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D014409:Tumor Necrosis Factor-alpha; D015016:Yohimbine; D000068438:Brimonidine Tartrate; D009638:Norepinephrine