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A. Introduction

  1. Chemokines are cytokines with chemoattractant activities for leukocytes
  2. Common structural motifs defining new superfamily of proteins
  3. At least four families of chemokines exist
    1. Alpha-chemokines - four cysteines, with two C-X-C motifs where X is any amino acid
    2. Beta-chemokines - four cysteines, with first two cysteines adjacent (C-C motifs)
    3. Lymphotactin - two cysteines only
    4. Fractalkine - first two cysteines separated by three amino acids
  4. Proteins are 8-10K molecular weight, with 20-70% homology
  5. Receptors are coupled to G proteins, and often bind more than one chemokine ligand
  6. HIV and Chemokines
    1. CCR5 (receptor) is a coreceptor for macrophage-tropic HIV strains
    2. CXCR4 is a coreceptor for T cell tropic-HIV strains

B. Chemokine Receptors and Cell Types

  1. For each cell type, receptors found and known ligands are listed
  2. Neutrophil
    1. CXCR1: IL-8, GCP-2
    2. CXCR2: IL-8, GCP-2, GRO-a, GRO-b, GRO-g, ENA-78, NAP-2, LIX
  3. Eosinophil
    1. CCR1: MCP-3, MCP-4, MIP-1a, RANTES
    2. CCR3: MCP-3, MCP-4, eotaxin-1, eotaxin-2, RANTES
  4. Basophil
    1. CCR2: MCP-1, -2, -3, -4, -5
    2. CCR3: MCP-3, MCP-4, eotaxin-1, eotaxin-2, RANTES
  5. Monocyte
    1. CCR1: IL-8, GCP-2
    2. CCR2: MCP-1, -2, -3, -4, -5
    3. CCR5: MIP-1a, MIP-1b, RANTES (HIV coreceptor) [4]
    4. CCR8: I-309
    5. ???: MDC, HCC-1, TECK
    6. CX3CR1: Fractalkine
    7. CXCR4: SDF-1 (HIV coreceptor) [4]
  6. Dendritic Cell
    1. CCR1: IL-8, GCP-2
    2. CCR2: MCP-1, -2, -3, -4, -5
    3. CCR3: MCP-3, MCP-4, eotaxin-1, eotaxin-2, RANTES
    4. CCR4: TARC
    5. CCR5: MIP-1a, MIP-1b, RANTES
    6. CCR6: MIP-3a (LARC, Exodus-1)
    7. ???: MDC, TECK
    8. CXCR4: SDF-1
  7. Resting T Lymphocyte
    1. ???: PARC, DC-CK-1
    2. ???: Lymphotactin
    3. CXCR4: SDF-1
  8. Activated T Lymphocyte
    1. CCR1: IL-8, GCP-2
    2. CCR2: MCP-1, -2, -3, -4, -5
    3. CCR4: TARC
    4. CCR5: MIP-1a, MIP-1b, RANTES
    5. CCR7: MIP-3b (ELC)
    6. ???: PARC, SLC, 6CKine (Exodus-2)
    7. CX3CR1: Fractalkine
    8. CXCR3: IP-10, MIG, I-TAC
  9. Natural Killer Cell
    1. CCR2: MCP-1, -2, -3, -4, -5
    2. CCR5: MIP-1a, MIP-1b, RANTES
    3. CX3CR1: Fractalkine
    4. CXCR3: IP-10, MIG, I-TAC
  10. Chemokine Receptor Signalling
    1. G-protein coupled receptors (GPCR)
    2. Many of these receptors are linked to G proteins of the Gi (inhibitory) class
    3. Many chemokines signal with activation of Ras and Rho proteins (bind GTP)
    4. These proteins are involved in stimulating cell motility
    5. Chemokines also bind Duffy receptors on red blood cells and endothelium
    6. Likely that Duffy protein is used to "soak up" chemokines
    7. Chemokines can also bind heparan sulfate proteoglycans and be "soaked up" that way

C. Disease Pathophysiology

  1. Many inflammatory diseases can be characterized by their chemokine profiles
  2. There is reasonably good correlation between chemokines and Th1 versus Th2 classes
  3. The finding of particular cell types in specific inflammatory diseases correlates well with cytokine profiles
  4. Various infectious agents encode cytokines and/or chemokines and/or their receptors
    1. Poxviruses cenclode functional IL-1ß and IFNg recptors
    2. Herpesviruses often express chemokine receptor homologues
    3. Human herpesvirus 8 (HHV-8) encodes a constitutively active chemokine receptor analog
    4. HHV-6, HHV-8, and molluscum contagiosum virus encode CC chemokine homologues
  5. Redundancy of chemokines may make specific antagonists less effective [1]

References

  1. Charo IF and Ransohoff RM. 2006. NEJM. 354(6):610 abstract
  2. Luster AD. 1998. NEJM. 338(7):436 abstract
  3. Busse WW and Lemanske RF. 2001. NEJM. 344(5):350 abstract
  4. Hogan CM and Hammer SM. 2001. Ann Intern Med. 134(10):978 abstract