Oral corticosteroids decrease eosinophil and CC chemokine expression but increase neutrophil, IL-8, and IFN-gamma-inducible protein 10 expression in asthmatic airway mucosa.
BACKGROUND
Cytokines and chemokines have been implicated in the pathogenesis of asthma. Inhaled corticosteroids have been shown to decrease the number of eosinophils and to downregulate T H 2 cytokines but to increase neutrophils. The effect of corticosteroids on chemokine expression in asthma has not yet been investigated.


OBJECTIVE
We sought to investigate the effect of a 2-week course of oral corticosteroid (methylprednisolone, 40 mg/d) on the expression of CXC chemokines (IL-8 and IFN-gamma-inducible protein 10 [IP-10]) and CC chemokines (eotaxin and monocyte chemotactic proteins [MCPs] 1-4) in endoscopic biopsy specimens of 13 patients with moderate-to-severe asthma.


METHODS
CD3, major basic protein, and elastase immunoreactivities were monitored before and after treatment by using immunocytochemistry. Eotaxin, IL-8, IP-10, MCP-1, MCP-2, MCP-3, and MCP-4 mRNA expression in epithelium and submucosa were studied by using in situ hybridization.


RESULTS
Corticosteroids reduced the number of CD3-positive T cells and major basic protein-positive eosinophils ( P < .05), whereas the number of neutrophils were increased ( P < .05). Corticosteroids also reduced the number of eotaxin ( P < .05), MCP-3, and MCP-4 mRNA-positive cells ( P < .001) in the epithelium and subepithelium. However, corticosteroids caused a significant increase in the epithelial expression of IL-8 ( P < .001), IP-10 ( P < .05), and MCP-2 mRNAs ( P < .01). Corticosteroids had no effects on MCP-1 mRNA expression.


CONCLUSIONS
Our results demonstrate the dual nature of corticosteroids. Although corticosteroids can downregulate the expression of some asthma-associated chemokines, such as eotaxin, MCP-3, and MCP-4, they can also upregulate the expression of other chemokines, including IL-8, IP-10, and MCP-2. The failure of oral corticosteroids to inhibit IL-8 mRNA expression might contribute to persistent airway neutrophilia observed in patients with moderate-to-severe asthma, despite treatment with corticosteroids.
Fukakusa
Motonori
M
Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Bergeron
Celine
C
Tulic
Meri K
MK
Fiset
Pierre-Olivier
PO
Al Dewachi
Oday
O
Laviolette
Michel
M
Hamid
Qutayba
Q
Chakir
Jamila
J
D000284:Administration, Oral; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D054357:Chemokine CXCL10; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D004804:Eosinophils / Q000473:pathology*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000627:therapeutic use; D009504:Neutrophils / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D005938:Glucocorticoids; D016209:Interleukin-8; D012333:RNA, Messenger; D008775:Methylprednisolone