Compositions and methods for modulating interleukin-10
The present invention provides compositions and methods for upregulating IL-10 production in a stimulated cell. In one aspect, the invention provides methods of identifying ERK activating agents capable of activating and amplifying the ERK MAPK pathway in a cell. Such ERK activating agents are capable of upregulating the production of IL-10 in stimulated cells. In another aspect, the invention provides ERK activating agents identified by the screening methods of the invention. Methods are also provided for preventing and treating inflammation in a susceptible patient by administering to the patient, a therapeutically effective amount of an ERK activating agent identified in accordance with the invention.
1. A method of upregulating IL-10 production above that in resting cells in a macrophage-like cell in response to an inflammatory stimulus comprising contacting said cell with a composition comprising an extracellular-signal-regulated kinase (ERK) activating agent in combination with a phosphatase inhibitor wherein the ERK activating agent is selected from colony stimulating factor 1 (CSF-1) or immune complexes (IC) wherein the macrophage-like cell is selected from the group consisting of bone marrow derived macrophages, leukocytes and dendritic cells and wherein the immune complexes are IgG immune complexes.
2. The method of claim 1 wherein the phosphatase inhibitor is selected from the group consisting of okadaic acid, sodium orthovanadate, NaVa4, cnataridin, 1 naphthyphosphate sodium salt, Na 3 VO 4 , NaF, b-glycerphosphate, rapamycin and tacrolimus.
3. The method of claim 1 wherein the inflammatory stimulus is selected from the group consisting of CD40-L, bacteria or bacterial components.
4. The method of claim 3 wherein the bacterial components are bacterial cell walls such as lipopolysaccharide (LPS) or lipotechoic acid.
5. The method of claim 1 wherein upregulation of IL-10 production is sustained for at least 30 minutes.
6. The method of claim 1 wherein the immune complexes are E-IgG.
7. The method of claim 1 wherein the immune complexes are soluble.
8. The method of claim 7 wherein the soluble immune complexes are Ig-OVA.