Cutaneous injection of human subjects with macrophage inflammatory protein-1 alpha induces significant recruitment of neutrophils and monocytes.
Macrophage inflammatory protein (MIP-1 alpha), a member of the CC chemokine subfamily, has been shown to attract T cells and monocytes in vitro and to be expressed at sites of inflammation. Although the in vitro activities of MIP-1 alpha have been well documented, the in vivo biological activities of MIP-1 alpha in humans have not been studied. To address this, we challenged human subjects by intradermal injection with up to 1000 pmol of MIP-1 alpha and performed biopsies 2, 10, and 24 h later. Although no acute cutaneous or systemic reactions were noted, endothelial cell activation, as indicated by the expression of E-selectin, was observed. In agreement with its in vitro activity, monocyte, lymphocyte, and, to a lesser degree, eosinophil infiltration was observed, peaking at 10-24 h. Surprisingly, in contrast to its reported lack of in vitro neutrophil-stimulating activity, a rapid infiltration of neutrophils was observed in vivo. This neutrophil infiltration occurred as early as 2 h, preceding the appearance of other cells, and peaked at 10 h. Interestingly, we found that neutrophils in whole blood, but not after isolation, expressed CCR1 on their cell surface. This CCR1 was thought to be functional as assessed by neutrophil CD11b up-regulation following whole-blood MIP-1 alpha stimulation. These studies substantiate the biological effects of MIP-1 alpha on monocytes and lymphocytes and uncover the previously unrecognized activity of MIP-1 alpha to induce neutrophil infiltration and endothelial cell activation, underscoring the need to evaluate chemokines in vivo in humans.
Lee
S C
SC
Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.
Brummet
M E
ME
Shahabuddin
S
S
Woodworth
T G
TG
Georas
S N
SN
Leiferman
K M
KM
Gilman
S C
SC
Stellato
C
C
Gladue
R P
RP
Schleimer
R P
RP
Beck
L A
LA
D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D054407:Chemokine CCL4; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007271:Injections, Intradermal; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage* / Q000494:pharmacology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis; D012867:Skin / Q000166:cytology
C515300:CCR1 protein, human; D054407:Chemokine CCL4; D019040:E-Selectin; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine