The role of peptides as therapeutic agents has gained considerable importance recently, and more than 7000 natural peptides have been reported which play a pivotal role in human physiology and have different applications such as, vaccines, and other immunotherapeutics [
1]. However, in addition to the desired action, these peptides may show undesirable immuno-activity, for example B cell or T cell activation and other proinflammatory events [
2‐
4]. Similarly in nature, different infectious agents also harbor immunomodulatory properties present in their proteins, which help them in initiation and progression of the disease [
5,
6]. Several examples of proinflammatory reactions are known where the pathogens get advantage of inflammation caused by their antigen. A well-known example is the proinflammatory response induced by the peptide Hp(2–20) of
Helicobacter pylori which induces proinflammatory activities such as, recruiting and activating various immune cells like neutrophils and monocytes, upregulation of integrins (Mac-1) and activation of the oxygen radical producing NADPH-oxidase. This leads to destruction of host mucosal tissue along with reduction in the viability and function of antineoplastic lymphocytes [
7]. Similarly, the peptide gG-2p20, which corresponds to amino acids 190–205 of glycoprotein G-2 of Herpes Simplex Virus-2 (HSV-2), induces proinflammatory effects by recruiting and activating the phagocytic cells. This, in turn, leads to reduced function and viability of NK cells [
8]. Since NK cells constitute early line of defense and particularly important in protection against HSV-2, such proinflammatory reaction caused by gG-2p20 peptide leads to HSV-2 infection. Furthermore, there are examples of other physiological diseases, such as transmissible spongiform encephalopathies (TSEs), where prion peptide PrP(106–126) increases the pathogenicity due to its proinflammatory nature [
9]. Similarly, LL-37, a 37 amino acid proinflammatory peptide generated from hCAP18 protein, has a role in pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis etc. [
10]. Another example of proinflammatory peptide is C-peptide, a cleavage product of proinsulin which is used in peptide-therapeutics. It has a proinflammatory response in different tissues and this property leads to inflammation in kidney and vasculature, worsening the disease in long term [
11].
The above evidences of proinflammatory property of peptide sequences underscore the correlation between amino acid sequence and its proinflammatory behavior. To the best of authors knowledge, there are no computational studies reported till date where any sequence-based signature or feature has been investigated which could be responsible for proinflammatory behavior of a peptide. Although, several studies have focused on the prediction of different kind of immune epitopes, such as B cell epitopes [
12‐
14], T cell epitopes [
15‐
17], MHC binders [
18], IL4-inducing peptides [
19], IFN-gamma inducing MHC binders [
20] and allergenicity [
21,
22], there is no study known where the sequence-based features have been examined to determine the proinflammatory nature of peptides. In this work, we have analyzed amino acid sequence of experimentally validated proinflammatory epitopes (PiEs) in contrast to non-proinflammatory epitopes (NPiEs) and developed a machine learning-based classification method incorporating the sequence-based features, to predict the proinflammatory nature of peptides and proteins.