PMID- 9029455
OWN - NLM
STAT- MEDLINE
DCOM- 19970404
LR  - 20220316
IS  - 0022-3492 (Print)
IS  - 0022-3492 (Linking)
VI  - 68
IP  - 1
DP  - 1997 Jan
TI  - Phenytoin and cyclosporine A specifically regulate macrophage phenotype and 
      expression of platelet-derived growth factor and interleukin-1 in vitro and in 
      vivo: possible molecular mechanism of drug-induced gingival hyperplasia.
PG  - 73-83
AB  - Phenytoin (pht) is an anticonvulsant drug commonly used for the prevention of 
      seizures. A common side effect of PHT therapy is gingival hyperplasia, 
      occasionally so severe that it requires surgical intervention. Cyclosporine A 
      (CSA) is a drug widely used for the control of rejection phenomena following 
      solid organ and bone marrow transplantation. A frequent side effect of CSA 
      administration is gingival overgrowth. As yet, the molecular mechanisms of 
      drug-induced gingival hyperplasia are unknown although it has been postulated 
      that certain drugs increase fibroblastic activity through alterations in levels 
      of various growth factors and cytokines. The purpose of this study was to: 1) 
      evaluate monocyte/macrophage platelet-derived growth factor (PDGF) and 
      interleukin (IL)-1 beta production in vitro after exposure to CSA; 2) determine 
      the levels of PDGF-B and IL-1 beta gene expression in minimally inflamed gingival 
      tissues of control patients and PHT-treated patients exhibiting gingival 
      overgrowth as well as patients with severe gingival inflammation; and 3) combine 
      characterization of macrophage phenotype with clinical presentation and 
      expression of PDGF-B and IL-1 beta in gingival tissues from the control and 
      PHT-treated patients. For the in vitro studies, commercial ELISA kits were used 
      to measure PDGF-A/PDGF-B and IL-1 beta levels in conditioned media from rat and 
      human monocyte/macrophage cell cultures. CSA caused a significant elevation of 
      PDGF but did not cause any changes in IL-1 beta levels. For the in vivo studies, 
      quantitative competitive reverse transcription polymerase chain reaction 
      (QC-RTPCR) techniques were utilized to measure PDGF-B and IL-1 beta mRNA levels 
      in experimental groups. PHT-treated patients exhibiting gingival overgrowth 
      demonstrated a significant increase in PDGF-B mRNA compared with minimally 
      inflamed controls. Patients with severe gingival inflammation also demonstrated a 
      significant increase in PDGF-B mRNA however, PHT-induced PDGF-B upregulation is 
      approximately 6 times larger than PDGF-B upregulation produced by inflammation 
      alone. PHT-treated patients exhibiting gingival overgrowth demonstrated no 
      significant increase in IL-1 beta mRNA; however, IL-1 beta mRNA levels in the 
      severely inflamed gingival samples demonstrated a significant increase. 
      Additionally, for the clinical samples, macrophage phenotype was characterized 
      immunohistochemically in adjacent sections using specific monoclonal antibodies 
      for inflammatory and reparative/proliferative phenotypes. There were no 
      significant differences in the numbers of either macrophage phenotype in 
      minimally inflamed gingival tissues; however, in the severely inflamed tissue, 
      there was a significant increase in the inflammatory macrophage phenotype and in 
      the hyperplastic gingival tissue, there was a significant increase in the 
      reparative/proliferative macrophage phenotype. The results of this investigation 
      indicate that the clinical presentation of inflamed and hyperplastic gingival 
      tissues is associated with specific macrophages phenotypes which express the 
      pro-inflammatory cytokine IL-1 beta in inflamed tissues or the essential 
      polypeptide growth factor PDGF-B in PHT-induced hyperplastic tissues.
FAU - Iacopino, A M
AU  - Iacopino AM
AD  - Department of Biomedical Sciences, Baylor College of Dentistry, Dallas, TX 
      75266-0677, USA.
FAU - Doxey, D
AU  - Doxey D
FAU - Cutler, C W
AU  - Cutler CW
FAU - Nares, S
AU  - Nares S
FAU - Stoever, K
AU  - Stoever K
FAU - Fojt, J
AU  - Fojt J
FAU - Gonzales, A
AU  - Gonzales A
FAU - Dill, R E
AU  - Dill RE
LA  - eng
GR  - R03 DE11181-02/DE/NIDCR NIH HHS/United States
GR  - R29 DE11553-01/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Periodontol
JT  - Journal of periodontology
JID - 8000345
RN  - 0 (Anticonvulsants)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-1)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (RNA, Messenger)
RN  - 6158TKW0C5 (Phenytoin)
RN  - 83HN0GTJ6D (Cyclosporine)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Anticonvulsants/*toxicity
MH  - Cells, Cultured
MH  - Cyclosporine/*toxicity
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Gingival Hyperplasia/*chemically induced/*metabolism
MH  - Humans
MH  - Immunophenotyping
MH  - Immunosuppressive Agents/*toxicity
MH  - Interleukin-1/*biosynthesis
MH  - Macrophages/*drug effects/immunology/metabolism
MH  - Middle Aged
MH  - Phenytoin/*toxicity
MH  - Platelet-Derived Growth Factor/*biosynthesis
MH  - RNA, Messenger/analysis
MH  - Rats
EDAT- 1997/01/01 00:00
MHDA- 1997/01/01 00:01
CRDT- 1997/01/01 00:00
PHST- 1997/01/01 00:00 [pubmed]
PHST- 1997/01/01 00:01 [medline]
PHST- 1997/01/01 00:00 [entrez]
AID - 10.1902/jop.1997.68.1.73 [doi]
PST - ppublish
SO  - J Periodontol. 1997 Jan;68(1):73-83. doi: 10.1902/jop.1997.68.1.73.