CD40 and OX40 ligand are increased on stimulated asthmatic airway smooth muscle.
BACKGROUND
Severe, persistent asthma is characterized by airway smooth muscle hyperplasia, inflammatory cell infiltration into the smooth muscle, and increased expression of many cytokines, including IL-4, IL-13, IL-1beta, and TNF-alpha. These cytokines have the potential to alter the expression of surface receptors such as CD40 and OX40 ligand on the airway smooth muscle cell.


OBJECTIVE
To examine whether cytokines alter expression of CD40 and OX40 ligand on airway smooth muscle cells and identify any differences in response between asthmatic and nonasthmatic airway smooth muscle cells.


METHODS
We used flow cytometry and immunohistochemistry to detect CD40 and OX40 ligand on airway smooth muscle cells cultured in the presence of TNF-alpha, IL-1beta, IL-4, or IL-13. Prostaglandin E 2 levels were assessed by ELISA.


RESULTS
TNF-alpha increased expression of both CD40 and OX40 ligand on both asthmatic and nonasthmatic airway smooth muscle cells. The level of expression was significantly greater on the asthmatic cells. IL-1beta alone had no effect, but it attenuated the TNF-induced expression of both CD40 and OX40 ligand. The mechanism of inhibition was COX-dependent for CD40 and was COX-independent but cyclic AMP-dependent for OX40 ligand. IL-4 and IL-13 had no effect.


CONCLUSIONS
Our study has demonstrated that TNF-alpha and IL-1beta have the potential to modulate differentially the interactions between cells present in the inflamed airways of a patient with asthma and therefore to contribute to the regulation of airway inflammation and remodeling.
Burgess
Janette K
JK
Department of Pharmacology, University of Sydney, Sydney, NSW, Australia. janette@pharmacol.usyd.edu.au
Blake
Anita E
AE
Boustany
Sarah
S
Johnson
Peter R A
PR
Armour
Carol L
CL
Black
Judith L
JL
Hunt
Nicholas H
NH
Hughes
J Margaret
JM
D000328:Adult; D000368:Aged; D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D015232:Dinoprostone / Q000502:physiology; D004338:Drug Combinations; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D053278:OX40 Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019013:CD40 Antigens; D016207:Cytokines; D004338:Drug Combinations; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053278:OX40 Ligand; C089251:TNFSF4 protein, human; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015232:Dinoprostone