Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological and immunohistochemical parameters.
BACKGROUND
Phosphorylase kinase (PhK), also known as adenosine triphosphate (ATP)-phosphorylase b phosphotransferase, integrates multiple calcium/calmodulin-dependent signalling pathways, including those involved in cell migration and cell proliferation, while coupling these pathways to glycogenolysis and ATP-dependent phosphorylation, thus ensuring continuing energy supply for these activities.


OBJECTIVE
Our laboratory recently reported correlation of elevated PhK activity with psoriatic activity. This study further evaluates the significance of drug-induced suppression of PhK activity on psoriatic activity.


METHODS
PhK activity was assayed in four groups, each with 10 patients: (i) active untreated psoriasis; (ii) resolving psoriasis treated by calcipotriol (Dovonex(R), Bristol Myers Squibb, Princeton, NJ, U.S.A. ), a vitamin D3 analogue and an indirect inhibitor of PhK; (iii) curcumin (diferuloylmethane), a selective PhK inhibitor; and (iv) 10 normal non-psoriatic subjects.


RESULTS
PhK activity in units mg-1 protein was highest in active untreated psoriasis (1204 +/- 804.3; mean +/- SD), lower in the calcipotriol-treated group (550.7 +/- 192. 9), lower in curcumin-treated group (207.2 +/- 97.6), and lowest in normal skin (105.4 +/- 44.6). One-way analysis of variance performed on log-transformed PhK activity measure showed significant differences among the four groups, F3,36 = 48.79, P < 0.0001. Decreased PhK activity in curcumin-and calcipotriol-treated psoriasis was associated with corresponding decreases in keratinocyte transferrin receptor (TRR) expression, severity of parakeratosis and density of epidermal CD8+ T cells.


CONCLUSIONS
Our results demonstrate that drug-induced suppression of PhK activity is associated with resolution of psoriatic activity as assessed by clinical, histological and immunohistochemical criteria, and support the hypothesis that effective antipsoriatic activity may be achieved through modulation of PhK activity.
Heng
M C
MC
Division of Dermatology, Department of Medicine, UCLA San Fernando Valley Program, VA Greater Los Angeles Healthcare System (Sepulveda), 16111 Plummer Street, Sepulveda, CA 91343, USA.
Song
M K
MK
Harker
J
J
Heng
M K
MK
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002117:Calcitriol / Q000031:analogs & derivatives / Q000627:therapeutic use; D002455:Cell Division; D003474:Curcumin / Q000627:therapeutic use; D003879:Dermatologic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010241:Parakeratosis / Q000188:drug therapy; D010764:Phosphorylase Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011990:Receptors, Transferrin / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003879:Dermatologic Agents; D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; D019394:Ki-67 Antigen; D011990:Receptors, Transferrin; C055085:calcipotriene; D010764:Phosphorylase Kinase; D002117:Calcitriol; D003474:Curcumin