The Influence of Interleukin-4 on Ligament Healing

Overview

Journal Wound Repair Regen

Date 2011 Apr 27

PMID 21518087

Citations 10

Authors

Connie S Chamberlain

Ellen M Leiferman

Kayt E Frisch

Sijian Wang

Xipei Yang

Stacey L Brickson

Ray Vanderby

Affiliations

Soon will be listed here.

Abstract

Despite a complex cascade of cellular events to reconstruct the damaged extracellular matrix, ligament healing results in a mechanically inferior scarred ligament. During normal healing, granulation tissue expands into any residual normal ligamentous tissue (creeping substitution), resulting in a larger region of healing, greater mechanical compromise and an inefficient repair process. To control creeping substitution and possibly enhance the repair process, the antiinflammatory cytokine, interleukin-4 (IL-4), was administered to rats before and after rupture of their medial collateral ligaments. In vitro experiments showed a time-dependent effect on fibroblast proliferation after IL-4 treatment. In vivo treatments with IL-4 (100 ng/mL IV) for 5 days resulted in decreased wound size and type III collagen and increased type I procollagen, indicating a more regenerative early healing in response to the IL-4 treatment. However, continued treatment of IL-4 to day 11 antagonized this early benefit and slowed healing. Together, these results suggest that IL-4 not only influences the macrophages and T lymphocytes but also stimulates fibroblasts associated with the proliferative phase of healing in a dose-, cell-, and time-dependent manner. Although treatment significantly influenced healing in the first week after injury, IL-4 alone was unable to maintain this early regenerative response.

Citing Articles

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Chamberlain C, Clements A, Kink J, Choi U, Baer G, Halanski M Stem Cells. 2019; 37(5):652-662.

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Impacts of Interleukin-17 Neutralization on the Inflammatory Response in a Healing Ligament.

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References

Bedi A, Fox A, Kovacevic D, Deng X, Warren R, Rodeo S . Doxycycline-mediated inhibition of matrix metalloproteinases improves healing after rotator cuff repair. Am J Sports Med. 2009; 38(2):308-17. DOI: 10.1177/0363546509347366. View

Volpert O, Fong T, Koch A, Peterson J, Waltenbaugh C, Tepper R . Inhibition of angiogenesis by interleukin 4. J Exp Med. 1998; 188(6):1039-46. PMC: 2212547. DOI: 10.1084/jem.188.6.1039. View

Provenzano P, Martinez D, Grindeland R, Dwyer K, Turner J, Vailas A . Hindlimb unloading alters ligament healing. J Appl Physiol (1985). 2002; 94(1):314-24. DOI: 10.1152/japplphysiol.00340.2002. View

Singer A, Clark R . Cutaneous wound healing. N Engl J Med. 1999; 341(10):738-46. DOI: 10.1056/NEJM199909023411006. View

Postlethwaite A, Holness M, Katai H, Raghow R . Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest. 1992; 90(4):1479-85. PMC: 443194. DOI: 10.1172/JCI116015. View

Vannier E, Miller L, Dinarello C . Coordinated antiinflammatory effects of interleukin 4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1992; 89(9):4076-80. PMC: 525635. DOI: 10.1073/pnas.89.9.4076. View

Buttner C, Skupin A, Reimann T, Rieber E, Unteregger G, Geyer P . Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: macrophages as a prominent source of interleukin-4. Am J Respir Cell Mol Biol. 1997; 17(3):315-25. DOI: 10.1165/ajrcmb.17.3.2279. View

Lowenthal J, Castle B, Christiansen J, Schreurs J, Rennick D, Arai N . Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. J Immunol. 1988; 140(2):456-64. View

Murphy P, Loitz B, Frank C, Hart D . Influence of exogenous growth factors on the expression of plasminogen activators by explants of normal and healing rabbit ligaments. Biochem Cell Biol. 1993; 71(11-12):522-9. DOI: 10.1139/o93-075. View

10.

Murray M, Spindler K, Abreu E, Muller J, Nedder A, Kelly M . Collagen-platelet rich plasma hydrogel enhances primary repair of the porcine anterior cruciate ligament. J Orthop Res. 2006; 25(1):81-91. DOI: 10.1002/jor.20282. View

11.

Tang J, Cao Y, Zhu B, Xin K, Wang X, Liu P . Adeno-associated virus-2-mediated bFGF gene transfer to digital flexor tendons significantly increases healing strength. an in vivo study. J Bone Joint Surg Am. 2008; 90(5):1078-89. DOI: 10.2106/JBJS.F.01188. View

12.

Haas C, Amin M, Allen B, Ruth J, Haines 3rd G, Woods J . Inhibition of angiogenesis by interleukin-4 gene therapy in rat adjuvant-induced arthritis. Arthritis Rheum. 2006; 54(8):2402-14. DOI: 10.1002/art.22034. View

13.

Lin T, Cardenas L, Soslowsky L . Biomechanics of tendon injury and repair. J Biomech. 2004; 37(6):865-77. DOI: 10.1016/j.jbiomech.2003.11.005. View

14.

Chamberlain C, Crowley E, Vanderby R . The spatio-temporal dynamics of ligament healing. Wound Repair Regen. 2009; 17(2):206-15. PMC: 3214965. DOI: 10.1111/j.1524-475X.2009.00465.x. View

15.

Allen J, Wong H, Costa G, Bienkowski M, Wahl S . Suppression of monocyte function and differential regulation of IL-1 and IL-1ra by IL-4 contribute to resolution of experimental arthritis. J Immunol. 1993; 151(8):4344-51. View

16.

Miossec P, Briolay J, Dechanet J, Wijdenes J, Martinez-Valdez H, Banchereau J . Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin-4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum. 1992; 35(8):874-83. DOI: 10.1002/art.1780350805. View

17.

Gillery P, Fertin C, Nicolas J, Chastang F, Kalis B, Banchereau J . Interleukin-4 stimulates collagen gene expression in human fibroblast monolayer cultures. Potential role in fibrosis. FEBS Lett. 1992; 302(3):231-4. DOI: 10.1016/0014-5793(92)80448-p. View

18.

Huaux F, Liu T, McGarry B, Ullenbruch M, Phan S . Dual roles of IL-4 in lung injury and fibrosis. J Immunol. 2003; 170(4):2083-92. DOI: 10.4049/jimmunol.170.4.2083. View

19.

Ando M, Miyazaki E, Fukami T, Kumamoto T, Tsuda T . Interleukin-4-producing cells in idiopathic pulmonary fibrosis: an immunohistochemical study. Respirology. 1999; 4(4):383-91. DOI: 10.1046/j.1440-1843.1999.00209.x. View

20.

Woo S, Abramowitch S, Kilger R, Liang R . Biomechanics of knee ligaments: injury, healing, and repair. J Biomech. 2005; 39(1):1-20. DOI: 10.1016/j.jbiomech.2004.10.025. View