Section 9
Chapter 8,307

Chemoattractants induce rapid release of the interleukin 1 type II decoy receptor in human polymorphonuclear cells

Colotta, F.; Orlando, S.; Fadlon, E.J.; Sozzani, S.; Matteucci, C.; Mantovani, A.

Journal of Experimental Medicine 181(6): 2181-2186


ISSN/ISBN: 0022-1007
PMID: 7760005
DOI: 10.1084/jem.181.6.2181
Accession: 008306913

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Molecules representative of different classes of chemotactic agents, including formyl-Met-Leu-Phe (FMLP), C5a, leukotriene B-4, platelet-activating factor, and interleukin (IL)-8, caused a rapid reduction in the IL-1 binding capacity by human polymorphonuclear leukocytes (PMN), a cell type expressing predominantly the IL-1 type II decoy receptor (IL-1 decoy RII). N-t-Boc-Met-Leu-Phe, an antagonist for the FMLP receptor, inhibited the loss of IL-1 binding capacity induced by FMLP. Monocyte chemotactic protein 1, a chemokine related to IL-8 but inactive on PMN, had no effect on IL-1 binding in this cell type. FMLP was selected for further detailed analysis of chemoattractant-induced loss of IL-1 binding by PMN. The action of FMLP was rapid, reaching 50% of its maximum (80%) at 30 s, the earliest measurable time point, and plateauing between 10 and 30 min. Dose-response analysis revealed that maximal reduction of IL-1 binding was reached at FMLP concentrations that were also optimal for chemotaxis (50% effective dose = 5 times 10-9 M). The loss of IL-1 binding capacity caused by FMLP was determined by a reduction in receptor number with no change in their affinity. The effect of FMLP on IL-1 receptor (IL-1R) was selective in that the PMN surface structures IL-8R, CD16, CD18, and major histocompatibility complex class I antigens were unaffected under these conditions. Loss of surface IL-1R was not due to an augmented rate of internalization. FMLP caused rapid release of a 45-kD IL-1-binding molecule identified as the IL-1 decoy RII. After FMLP-induced release, PMN reexpressed newly synthesized receptors, reaching basal levels by 4 h. FMLP-induced release of the IL-1 decoy PII did not impair the responsiveness of PMN to IL-1 in terms of promotion of survival and cytokine production. FMLP-induced release of the IL-1 decoy RII was unaffected by protein synthesis inhibitors, was blocked by certain protease inhibitors, and was mimicked by agents (the Ca-2+ ionophore A23187 and phorbol myristate acetate) that recapitulate elements in the signal transduction pathway of chemoattractant receptors. The time frame and concentration range of chemoattractant-induced rapid release of the IL-1 decoy RII are consistent with the view that IL-1 decoy RII release is an early event in the multistep process of leukocyte recruitment. Rapid chemoattractant-induced IL-1 decoy RII release in the circulation may counteract IL-1 leaking into the systemic circulation from sites of inflammation while preserving the capacity of leukocytes to respond to IL-1 in tissues. This phenomenon may contribute as well to the antiinflammatory effect of systemic administration of chemotactic agents.

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