CCL2 as a trigger of manifestations of compensatory anti-inflammatory response syndrome in mice with severe systemic inflammatory response syndrome

Hitoshi Takahashi^*, Yasuhiro Tsuda^*, Makiko Kobayashi^*^,, David N. Herndon and Fujio Suzuki^*^,^,1

^* Department of Internal Medicine, The University of Texas Medical Branch, Galveston; and
Shriners Hospitals for Children, Galveston, Texas

¹Correspondence: The University of Texas Medical Branch, Department of Internal Medicine, 301 University Boulevard, Galveston, TX 77555-0435. E-mail: fsuzuki{at}utmb.edu

Patients with compensatory anti-inflammatory response syndrome(CARS) are at a higher risk for infection with various opportunisticpathogens. CARS develops commonly in association with the manifestationof systemic inflammatory response syndrome (SIRS). In the presentstudy, the role of SIRS-associated soluble factors on the CARSdevelopment was examined in mice with pancreatitis, a carrierof typical SIRS. Following the production of SIRS-related cytokines[tumor necrosis factor ${alpha}$ and interleukin (IL)-1ß],CC chemokine ligand 2 (CCL2), IL-4, and IL-10 (typical CARScytokines) were detected in the sera of mice with pancreatitis.CCL2 has been described as an essential chemokine for the Thelper cell type 2 manifestation. CARS effector cells (cellswith an ability to produce IL-4 and IL-10) were not generatedfrom normal T cells after stimulation with SIRS-related cytokines.However, these cells were generated from normal T cells aftercultivation with peripheral blood neutrophils (PMN) from SIRSmice in a dual-chamber transwell. Normal T cells did not convertto CARS effector cells after transwell cultures with PMN fromnormal mice. CCL2 was detected in culture fluids of PMN fromSIRS mice, and PMN from normal mice did not produce CCL2 intotheir culture fluids. CARS effector cells did not appear inPMN-depleted SIRS mice or SIRS mice treated with anti-CCL2 monoclonalantibody, and these cells were demonstrated in PMN-depletedSIRS mice after treatment with recombinant murine CCL2. Theseresults indicate that CCL2 produced by PMN from SIRS mice isan active molecule on the SIRS-associated CARS manifestation.

Key Words: SIRS • CARS • neutrophils