Alpha-chemokine-mediated signal transduction in human Kaposi's sarcoma spindle cells.
The role of chemokines and their receptors in HIV biology and Kaposi's sarcoma (KS) pathogenesis has recently gained considerable attention. It has been shown that KS-associated human herpes virus type 8 (KSHV/HHV-8) encodes functional homologues of certain chemokines and chemokine receptors. This suggests that chemokines may contribute to the growth and spread of KS seen in AIDS. We found the expression of CXCR4 in primary KS tissue by using in situ hybridization (ISH). Recently, alpha-chemokine receptors CXCR1 and CXCR2 have also been shown to be expressed by KS tissues. We further characterized the expression of these chemokines as well as the signaling events induced upon binding to their respective cognate ligands in the KS 38 spindle cell line. These cells express authentic characteristics of primary KS spindle cells and provide a useful in vitro model for these studies. We observed using RT-PCR that KS 38 cells express mRNA for the alpha-chemokine receptors CXCR1, CXCR2, and CXCR4. We also confirmed the cell surface protein expression by FACS analysis. Characterization of signaling pathways revealed that the alpha-chemokines, IL-8 and stromal cell-derived factor 1alpha (SDF1alpha/CXCL12), activated members of the mitogen-activated protein (MAP) kinase family, including Erk kinase, c-Jun amino terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 MAP kinase. Furthermore, using DNA protein-binding experiments, we have shown that IL-8 increased AP-1 and NF Kappa B activity in these cells. IL-8 also enhanced the chemotaxis of KS cells. These results reveal that chemokine-induced signaling pathways may mediate cell growth, transcriptional activation and cell migration in KS.
Wang
Jian-Feng
JF
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA.
Liu
Zhong-Ying
ZY
Anand
Appakkudal R
AR
Zhang
Xuefeng
X
Brown
Lawrence F
LF
Dezube
Bruce J
BJ
Gill
Parkash
P
Ganju
Ramesh K
RK
D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D002633:Chemotaxis; D004789:Enzyme Activation; D006801:Humans; D017403:In Situ Hybridization; D016209:Interleukin-8 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016209:Interleukin-8; D016328:NF-kappa B; D019718:Receptors, CXCR4; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases