PMID- 14656201
OWN - NLM
STAT- MEDLINE
DCOM- 20040224
LR  - 20190709
IS  - 0022-0795 (Print)
IS  - 0022-0795 (Linking)
VI  - 179
IP  - 3
DP  - 2003 Dec
TI  - The molecular and cellular basis of corticosteroid resistance.
PG  - 301-10
AB  - Corticosteroids (CS) can modulate gene expression and are often used to treat a 
      range of immunological and inflammatory diseases such as asthma, inflammatory 
      bowel disease and rheumatoid arthritis. However, a proportion of patients fail to 
      show an adequate response. On this basis patients have been subdivided into 
      CS-sensitive (SS) and -resistant (SR) subgroups. The ability of CS to inhibit 
      peripheral blood T cell proliferation in vitro has also been used similarly. In 
      rheumatoid arthritis (RA), the in vitro-defined SS and SR subgroups correlate 
      with the clinical responses to CS therapy. The mechanisms responsible for this 
      observation are unknown but they appear to involve a number of known molecular 
      events related to the described mechanisms of action of CS. These include 
      alterations in the functional status of CS receptor-alpha, perturbations of the 
      cytokine and hormonal milieu and intracellular signalling pathways. Peripheral 
      blood mononuclear cells (MNCs) from SR significantly overexpress activated 
      NF-kappaB. In vitro, CS fail to significantly inhibit concanavalin A 
      (conA)-induced NF-kappaB activation in MNCs from SR RA patients. The alterations 
      in the intracellular signalling pathways may explain in part our observations 
      seen in SR RA subjects, CS fail to significantly inhibit conA-induced interleukin 
      (IL)-2 and IL-4 secretion and lipopolysaccharide-induced IL-8 and IL-1beta 
      secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8 and 
      IL-1beta in RA patients. In asthma, CS fail to induce L10 in SR asthma patients. 
      Other molecular mechanisms such as enhanced AP-1 expression and alterations in 
      the MAP kinase pathway are most likely to be involved too and we are currently 
      investigating such possibilities. A full understanding of the molecular basis of 
      SR will lead to the development of more rational therapeutic strategies.
FAU - Chikanza, I C
AU  - Chikanza IC
AD  - Bone and Joint Research Unit, John Vane Building, St Bartholomew's and Royal 
      London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, 
      UK. i.c.chikanza@qmul.ac.uk
FAU - Kozaci, D
AU  - Kozaci D
FAU - Chernajovsky, Y
AU  - Chernajovsky Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - J Endocrinol
JT  - The Journal of endocrinology
JID - 0375363
RN  - 0 (Adrenal Cortex Hormones)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Cytokines)
RN  - 0 (Immunosuppressive Agents)
SB  - IM
MH  - Adrenal Cortex Hormones/*pharmacology
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Cytokines/drug effects
MH  - Drug Resistance/genetics
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Immunosuppressive Agents/pharmacology
MH  - Signal Transduction/drug effects
RF  - 55
EDAT- 2003/12/06 05:00
MHDA- 2004/02/26 05:00
CRDT- 2003/12/06 05:00
PHST- 2003/12/06 05:00 [pubmed]
PHST- 2004/02/26 05:00 [medline]
PHST- 2003/12/06 05:00 [entrez]
AID - 10.1677/joe.0.1790301 [doi]
PST - ppublish
SO  - J Endocrinol. 2003 Dec;179(3):301-10. doi: 10.1677/joe.0.1790301.