Increased levels of NF-kappaB inhibitors (IkappaBalpha and IkappaBgamma) in the intestinal mucosa of Crohn's disease patients during infliximab treatment.
The treatment with infliximab is employed successfully in Crohn's disease (CD) but predictors of efficacy are lacking. Activation of the transcription factor NF-kB has been demonstrated in CD and its inhibition is one of the mechanisms by which anti-inflammatory agents exert their effects. We evaluated the production of TNFalpha by peripheral blood mononuclear cells (PBMC) and the levels of NF-kappaB family molecules in the intestinal mucosa during infliximab therapy in 12 patients. TNFalpha was assayed on supernatants of PBMC culture stimulated with PHA or LPS. Immunohistochemistry was also done on intestinal biopsies. In six patients, Western blot analysis of the NF-kappaB subunit Rel-A, and its inhibitors IkappaBalpha and IkappaBgamma was performed on intestinal biopsies and PBMC. The TNFalpha production by LPS stimulated PBMC showed mild changes, while it was increased by PHA-stimulated PBMC after treatment. The number of inflammatory cells in the intestinal mucosa was reduced (p<0.002) by the treatment. In five out of six cases we detected an increase of the IkappaBalpha and IkappaBgamma)inhibitor levels in intestinal biopsies after treatment. An increase of IkappaB inhibitors levels could be one of the mechanisms by which infliximab decreases NF-kappaB activity and exerts its anti-inflammatory effects.
Guidi
L
L
Istituto di Medicina Interna, Università Cattolica del Sacro Cuore, Roma, Italy. lguidi@rm.unicatt.it
Costanzo
M
M
Ciarniello
M
M
De Vitis
I
I
Pioli
C
C
Gatta
L
L
Pace
L
L
Tricerri
A
A
Bartoloni
C
C
Coppola
L
L
Balistreri
P
P
Doria
G
G
Fedeli
G
G
Gasbarrini
G B
GB
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015153:Blotting, Western; D003424:Crohn Disease / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D020672:I-kappa B Proteins; C501943:IkappaBgamma protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010446:Peptide Fragments; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000069285:Infliximab