Regulation of CCR5 and CXCR4 expression by type 1 and type 2 cytokines: CCR5 expression is downregulated by IL-10 in CD4-positive lymphocytes.
HIV-1 transmission and disease progression is, in general, characterized by initial predominance of macrophage tropic, non-syncytium-inducing strains followed by a switch to T-cell tropic, syncytium-inducing strains. Using sensitive, quantitative kinetic RT-PCR, we examined cytokine regulation of tropism-specific HIV-1 coreceptor expression in PBMCs from HIV-1-seronegative individuals. Proinflammatory (TNF-alpha and IL-12) and type 1 cytokines (IFN-gamma and IL-2) significantly upregulated CCR5 (wt allele) mRNA expression in CCR5 homozygous wild-type (wt/wt) and heterozygous individuals (wt/del) (P < 0.02). CCR5 (wt) mRNA expression in unstimulated PBMCs was significantly increased in wt/wt individuals compared to that of wt/del individuals (P < 0.01). In wt/del individuals, del CCR5 mRNA was expressed at 10-fold greater levels than wt CCR5 mRNA in unstimulated PBMCs from the same individual. Flow cytometry confirmed that upregulated CCR5 mRNA following type 1 cytokine stimulation leads to increased cell surface expression of CCR5 protein. The type 2 cytokine IL-10 downregulated both CCR5 mRNA and protein expression in wt/wt and wt/del individuals. Proinflammatory, type 1, and type 2 cytokines significantly increased CXCR4 mRNA expression in wt/wt, wt/del, and del/del CCR5 genotypes (P < 0.02). These results suggest that changes in the cytokine milieu influence chemokine receptor expression and may explain emergence of tropism-specific strains facilitating HIV transmission and disease progression.
Patterson
B K
BK
Department of Obstetrics/Gynecology, Northwestern University Medical School, Chicago, Illinois 60611, USA. bpatters@nmh.org
Czerniewski
M
M
Andersson
J
J
Sullivan
Y
Y
Su
F
F
Jiyamapa
D
D
Burki
Z
Z
Landay
A
A
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D015658:HIV Infections / Q000209:etiology / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D007700:Kinetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014774:Virulence / Q000276:immunology
D016207:Cytokines; D017931:DNA Primers; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D016753:Interleukin-10