PEGylated IL-10 Activates Kupffer Cells to Control Hypercholesterolemia.
Interleukin-10 (IL-10) is a multifunctional cytokine that exerts potent context specific immunostimulatory and immunosuppressive effects. We have investigated the mechanism by which PEGylated rIL-10 regulates plasma cholesterol in mice and humans. In agreement with previous work on rIL-10, we report that PEGylated rIL-10 harnesses the myeloid immune system to control total plasma cholesterol levels. We have discovered that PEG-rMuIL-10's dramatic lowering of plasma cholesterol is dependent on phagocytotic cells. In particular, PEG-rHuIL-10 enhances cholesterol uptake by Kupffer cells. In addition, removal of phagocytotic cells dramatically increases plasma cholesterol levels, suggesting for the first time that immunological cells are implicitly involved in regulating total cholesterol levels. These data suggest that treatment with PEG-rIL-10 potentiates endogenous cholesterol regulating cell populations not currently targeted by standard of care therapeutics. Furthermore, we show that IL-10's increase of Kupffer cell cholesterol phagocytosis is concomitant with decreases in liver cholesterol and triglycerides. This leads to the reversal of early periportal liver fibrosis and facilitates the restoration of liver health. These data recommend PEG-rIL-10 for evaluation in the treatment of fatty liver disease and preventing its progression to non-alcoholic steatohepatitis. In direct confirmation of our in vivo findings in the treatment of hypercholesterolemic mice with PEG-rMuIL-10, we report that treatment of hypercholesterolemic cancer patients with PEG-rHuIL-10 lowers total plasma cholesterol by up to 50%. Taken together these data suggest that PEG-rIL-10's cholesterol regulating biology is consistent between mice and humans.
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Ivan H
IH
Chan
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Dennis
D
Van Hoof
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Marina
M
Abramova
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Melissa
M
Bilardello
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Elliot
E
Mar
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Brett
B
Jorgensen
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Scott
S
McCauley
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Harminder
H
Bal
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Martin
M
Oft
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
Peter
P
Van Vlasselaer
ARMO BioSciences, Inc., 575 Chesapeake Drive, Redwood City, CA, 94063, United States of America.
John B
http://orcid.org/0000-0002-8502-732X
JB
Mumm
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002784:Cholesterol / Q000097:blood* / Q000276:immunology; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007728:Kupffer Cells / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010587:Phagocytosis / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
D007155:Immunologic Factors; D011994:Recombinant Proteins; D016753:Interleukin-10; D011092:Polyethylene Glycols; D002784:Cholesterol