Signaling Proteins Are Represented in Tissue Fluid/Lymph from Soft Tissues of Normal Human Legs at Concentrations Different from Serum

Abstract

Background: The mobile intercellular fluid flowing to and in the lymphatics contains filtered plasma products and substances synthesized and excreted by tissue cells. Among them are signaling proteins such as cytokines, chemokines, enzymes, and growth factors. They act locally in autocrine and paracrine systems regulating cell metabolism, proliferation, and formation of the ground matrix. They play an immunoregulatory role in infections, wound healing, and tumor cell growth. Methods and Results: In this study we measured the concentration of selected cytokines, chemokines, tissue enzymes, and growth factors in tissue fluid/lymph drained from normal human leg soft tissues. Legs exposed to infections and trauma often result in development of lymphedema. Lymph was drained from superficial calf lymphatics using microsurgical techniques. Our studies showed generally higher concentrations of cytokines, chemokines, enzymes, and growth factors in lymph than in serum. The total protein L/S ratio was 0.22, whereas that of various lymph signaling proteins ranged between 1 and 10. Conclusions: This indicates that in addition to proteins filtered from blood, local cells contribute to lymph concentration by own production, depending on the actual cell requirement. Moreover, there were major individual differences of lymph levels with simultaneous stable serum levels. This suggests existence of a local autonomous regulatory humoral mechanism in tissues, not reflected in serum.

Hyperkeratosis in human lower limb lymphedema: the effect of stagnant tissue fluid/lymph

“…This could be accounted for by a lower level of cytokines responsible for the proliferation of KC in serum than in TF/L. 9 We also observed that there was a significant increase in the percentage of KC expressing the PCNA and Ki67 proliferation markers after culture in the lymphedema TF/L compared to those cultured in TF/L from healthy controls, 20% serum or RPMI (Fig. 3b,c).…”

“…Epidermis, in particular its basal layer, remains in a direct contact with mobile tissue fluid generated by the capillary plasma filtration process. This fluid contains humoral factors, which can have stimulatory or repressive regulatory properties on KC and fibroblasts . The composition of the TF/L differs from that of plasma, although it is the product of diffusion and filtration of plasma components.…”

“…Skin tissue fluid is rich in various types of cytokines and growth factors with concentrations higher in the prenodal lymph than in serum, due to the local production by keratinocytes, lymphocytes and macrophages. 8,9 The question remains open as to which of the many cytokines and growth factors present in TF/L is or are responsible for the stimulation of KC stem cells as well as of transit amplifying cells (TA) and, subsequently, for excessive keratinocyte proliferation. Identification and subsequent neutralization of the responsible cytokine(s) by intralymphatically administrated antibodies could be a therapeutic way of preventing proliferation of keratinocytes in lymphedema.…”

Lymphatic Network in Atherosclerosis: the Underestimated Path

“…We now know that a broad array of cytokines, proteins, growth factors are contained within lymphatic fluid, which play an important role in metabolism, proliferation, as well as an immunoregulatory role [54]. When comparing with serum concentrations, Zaleska  et al.…”

IL-6 regulates adipose deposition and homeostasis in lymphedema

“…In addition, previous studies have shown that the expression of IL-6 is increased in both primary and surgical models of lymphedema (20,28). Finally, a recent study has shown that the concentration of IL-6 is higher in lymph fluid as compared with subcutaneous fat, suggesting that the lymphatics play a role in transport or clearance of inflammatory cytokines (38).…”